Histone demethylase inhibitors

ABSTRACT

Provided herein are substituted pyrazolylpyridine, pyrazolylpyridazine, and pyrazolylpyrimidine derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma and the like.

CROSS REFERENCE

This application is a continuation application of U.S. application Ser.No. 14/630,091, filed Feb. 24, 2015, which is a divisional applicationof U.S. application Ser. No. 14/098,415, filed Dec. 5, 2013, now U.S.Pat. No. 8,987,461, issued on Mar. 24, 2015, which claims the benefit ofU.S. Provisional Application No. 61/784,414, filed Mar. 14, 2013, andU.S. Provisional Application No. 61/734,330, filed Dec. 6, 2012, thecontents of which are hereby incorporated by reference in theirentireties.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted pyrazolylpyridine derivative compoundsand pharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful for inhibition histonedemethylase. Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, bladder cancer, lung cancer and/or melanoma and the like. Thesubstituted pyrazolylpyridine derivative compounds described herein arebased upon a disubstituted pyridine ring bearing at the 4-position acarboxylic acid, carboxylic acid ester or carboxylic acid bioisosterethereof, and at the 2-position a substituted 1-pyrazolyl group.

One embodiment provides a compound of Formula (I) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   with the provision:-   if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,    trifluoromethyl, isopropyl or cyclopropyl; or-   if R¹ and R³ are both hydrogen, then R² is not methyl, or    trifluoromethyl; or-   if R¹ and R³ are both methyl, then R² is not hydrogen, methyl or    ethyl; or-   if R¹ and R² are hydrogen, then R³ is not

One embodiment provides a compound of Formula (II) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

One embodiment provides a compound of Formula (III) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is C₂-C₁₀ alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

One embodiment provides a compound of Formula (IV) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

One embodiment provides a compound of Formula (V) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I),Formula (II), Formula (III), Formula (IV), or Formula (V), or atautomer, stereoisomer, geometric isomer, N-oxide, or pharmaceuticallyacceptable salt thereof.

One embodiment provides a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I), Formula (II), Formula (III),Formula (IV), or Formula (V), or a tautomer, stereoisomer, geometricisomer, N-oxide, or pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

DEFINITIONS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises two to ten carbon atoms (e.g., C₂-C₁₀alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, carbocyclyl,carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond and having from two to twelve carbon atoms,for example, ethenylene, propenylene, n-butenylene, and the like. Thealkenylene chain is attached to the rest of the molecule through adouble bond or a single bond and to the radical group through a doublebond or a single bond. The points of attachment of the alkenylene chainto the rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkenylene chain is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substitutedwith one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and where each of the above substituentsis unsubstituted unless otherwise indicated.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hiickel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds.) A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R_(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical may be optionally substituted asdefined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. The heteroatoms in theheterocyclyl radical may be optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl may be attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclylwhere R^(c) is an alkylene chain as defined above. Ifthe heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclylis optionally attached to the alkyl radical at the nitrogen atom. Thealkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hiickeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

The compounds, or their pharmaceutically acceptable salts may containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers (e.g., cis or trans.) Likewise, all possibleisomers, as well as their racemic and optically pure forms, and alltautomeric forms are also intended to be included. The term “geometricisomer” refers to E or Z geometric isomers (e.g., cis or trans) of analkene double bond. The term “positional isomer” refers to structuralisomers around a central ring, such as ortho-, meta-, and para-isomersaround a benzene ring.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. It is therefore contemplated that variousstereoisomers and mixtures thereof and includes “enantiomers,” whichrefers to two stereoisomers whose molecular structures arenonsuperimposeable mirror images of one another.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedpyrazolylpyridine derivative compounds described herein is intended toencompass any and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997), which is hereby incorporated byreference in its entirety). Acid addition salts of basic compounds maybe prepared by contacting the free base forms with a sufficient amountof the desired acid to produce the salt according to methods andtechniques with which a skilled artisan is familiar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts may beformed with metals or amines, such as alkali and alkaline earth metalsor organic amines. Salts derived from inorganic bases include, but arenot limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein. Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. A prodrug may be inactive when administered to a subject,but is converted in vivo to an active compound, for example, byhydrolysis. The prodrug compound often offers advantages of solubility,tissue compatibility or delayed release in a mammalian organism (see,e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, may be prepared by modifying functional groups presentin the active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino ormercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, acetate, formateand benzoate derivatives of alcohol or amine functional groups in theactive compounds and the like.

Substituted Pyrazolylpyridine Derivative Compounds

Substituted pyrazolylpyridine derivative compounds are described hereinthat inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic disease. The compounds described herein may,therefore, be useful for treating prostate cancer, breast cancer,bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (I) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   with the provision:-   if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,    trifluoromethyl, isopropyl or cyclopropyl; or-   if R¹ and R³ are both hydrogen, then R² is not methyl, or    trifluoromethyl; or-   if R¹ and R³ are both methyl, then R² is not hydrogen, methyl or    ethyl; or-   if R¹ and R² are hydrogen, then R³ is not

Another embodiment provides a compound of Formula (I), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (I), whereinR⁴ is alkyl. Another embodiment provides a compound of Formula (I),wherein R³ is hydroxy. Another embodiment provides a compound of Formula(I), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides a compoundof Formula (I), wherein R³ is aralkyl. Another embodiment provides acompound of Formula (I), wherein R³ is —OR⁵. Another embodiment providesa compound of Formula (I), wherein —OR⁵ is carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl. Another embodimentprovides a compound of Formula (I), wherein —OR⁵ is aralkyl, orheteroarylalkyl. Another embodiment provides a compound of Formula (I),wherein —OR⁵ is carbocyclylalkyl, or heterocyclylalkyl. Anotherembodiment provides a compound of Formula (I), wherein R³ is aryl.Another embodiment provides a compound of Formula (I), wherein R¹ and R²are both hydrogen. Another embodiment provides a compound of Formula(I), wherein R¹ is hydrogen. Another embodiment provides a compound ofFormula (I), wherein R² is hydrogen. Another embodiment provides acompound of Formula (I), wherein R¹ and R² are both hydrogen. Anotherembodiment provides a compound of Formula (I), wherein R³ is phenylsubstituted by at least one substituent selected from alkyl, halogen,hydroxy, alkoxy or alkylsulfone. Another embodiment provides a compoundof Formula (I), wherein R³ is phenyl substituted at the 4-position.

One embodiment provides a compound of Formula (II) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (II), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (II),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(II), wherein R¹ or R² is alkyl. Another embodiment provides a compoundof Formula (II), wherein R¹ or R² is carbocyclyl. Another embodimentprovides a compound of Formula (II), wherein R¹ or R² is aryl. Anotherembodiment provides a compound of Formula (II), wherein R¹ or R² isaralkyl.

Another embodiment provides a compound of Formula (II), wherein R¹ ishydrogen. Another embodiment provides a compound of Formula (II),wherein R² is hydrogen. Another embodiment provides a compound ofFormula (II), wherein R¹ is alkyl. Another embodiment provides acompound of Formula (II), wherein R² is alkyl. Another embodimentprovides a compound of Formula (II), wherein R¹ and R² are alkyl.Another embodiment provides a compound of Formula (II), wherein R¹ iscarbocyclyl. Another embodiment provides a compound of Formula (II),wherein R² is carbocyclyl. Another embodiment provides a compound ofFormula (II), wherein R¹ is aryl. Another embodiment provides a compoundof Formula (II), wherein R² is aryl. Another embodiment provides acompound of Formula (II), wherein R¹ is aralkyl. Another embodimentprovides a compound of Formula (II), wherein R¹ is aralkyl and R² ishydrogen. Another embodiment provides a compound of Formula (II),wherein R¹ is aralkyl and the aralkyl comprises a C₁ alkylene group.Another embodiment provides a compound of Formula (II), wherein R¹ isaralkyl and the aralkyl comprises a C₁-C₃ alkylene group. Anotherembodiment provides a compound of Formula (II), wherein R¹ is aralkyland the aralkyl comprises an optionally substituted phenyl group.Another embodiment provides a compound of Formula (II), wherein R¹ isaralkyl and the aralkyl comprises a benzyl group. Another embodimentprovides a compound of Formula (II), wherein R² is aralkyl.

Another embodiment provides a compound of Formula (II), wherein R⁴ ishydrogen and R¹ is carbocyclylalkyl. Another embodiment provides acompound of Formula (II), wherein R⁴ is hydrogen and R² iscarbocyclylalkyl. Another embodiment provides a compound of Formula(II), wherein R⁴ is hydrogen and R¹ is hydrogen. Another embodimentprovides a compound of Formula (II), wherein R⁴ is hydrogen and R² ishydrogen. Another embodiment provides a compound of Formula (II),wherein R⁴ is hydrogen and R¹ is alkyl. Another embodiment provides acompound of Formula (II), wherein R⁴ is hydrogen and R² is alkyl.Another embodiment provides a compound of Formula (II), wherein R⁴ ishydrogen and R¹ is carbocyclyl. Another embodiment provides a compoundof Formula (II), wherein R⁴ is hydrogen and R² is carbocyclyl. Anotherembodiment provides a compound of Formula (II), wherein R⁴ is hydrogenand R¹ is aryl. Another embodiment provides a compound of Formula (II),wherein R⁴ is hydrogen and R² is aryl. Another embodiment provides acompound of Formula (II), wherein R⁴ is hydrogen and R¹ is aralkyl.Another embodiment provides a compound of Formula (II), wherein R⁴ ishydrogen, R¹ is aralkyl and R² is hydrogen. Another embodiment providesa compound of Formula (II), wherein R⁴ is hydrogen, R¹ is aralkyl andthe aralkyl comprises a C₁ alkylene group. Another embodiment provides acompound of Formula (II), wherein R⁴ is hydrogen, R¹ is aralkyl and thearalkyl comprises a C₁-C₃ alkylene group. Another embodiment provides acompound of Formula (II), wherein R⁴ is hydrogen, R¹ is aralkyl and thearalkyl comprises an optionally substituted phenyl group. Anotherembodiment provides a compound of Formula (II), wherein R⁴ is hydrogen,R¹ is aralkyl and the aralkyl comprises a benzyl group. Anotherembodiment provides a compound of Formula (II), wherein R² is aralkyl.Another embodiment provides a compound of Formula (II), wherein R⁴ ishydrogen, R¹ is carbocyclylalkyl. Another embodiment provides a compoundof Formula (II), wherein R⁴ is hydrogen and R² is carbocyclylalkyl.

One embodiment provides a compound of Formula (III) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is C₂-C₁₀ alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (III), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (III),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(III), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides acompound of Formula (III), wherein R³ is aryl. Another embodimentprovides a compound of Formula (III), wherein R³ is aralkyl.

One embodiment provides a compound of Formula (IV) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

Another embodiment provides a compound of Formula (IV), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (IV),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(IV), wherein R¹ and R² are hydrogen. Another embodiment provides acompound of Formula (IV), wherein X is C₁-C₄ alkylene. Anotherembodiment provides a compound of Formula (IV), wherein X is C₁-C₂alkylene. Another embodiment provides a compound of Formula (IV),wherein X is C₁ alkylene. Another embodiment provides a compound ofFormula (IV), wherein Y is hydrogen. Another embodiment provides acompound of Formula (IV), wherein Y is carbocyclyl. Another embodimentprovides a compound of Formula (IV), wherein Y is aryl. Anotherembodiment provides a compound of Formula (IV), wherein Y is a phenyl.Another embodiment provides a compound of Formula (IV), wherein Y isheteroaryl.

Another embodiment provides a compound of Formula (IV), wherein R¹ ishydrogen. Another embodiment provides a compound of Formula (IV),wherein R² is hydrogen. Another embodiment provides a compound ofFormula (IV), wherein R¹ and R² are hydrogen, and X is C₁-C₂ alkylene.Another embodiment provides a compound of Formula (IV), wherein R¹ andR² are hydrogen, and X is C₁ alkylene. Another embodiment provides acompound of Formula (IV), wherein R¹ and R² are hydrogen, X is C₁-C₂alkylene, and Y is a phenyl. Another embodiment provides a compound ofFormula (IV), wherein R¹ and R² are hydrogen, X is C₁ alkylene, and Y isa phenyl. Another embodiment provides a compound of Formula (IV),wherein R⁴ is hydrogen, R¹ and R² are hydrogen, X is C₁-C₂ alkylene, andY is a phenyl. Another embodiment provides a compound of Formula (IV),wherein R⁴ is hydrogen, R¹ and R² are hydrogen, X is C₁ alkylene, and Yis a phenyl. Another embodiment provides a compound of Formula (IV),wherein Y is a phenyl optionally substituted with an alkoxy, anaralkoxy, or a cycloalkylalkoxy. Another embodiment provides a compoundof Formula (IV), wherein Y is a phenyl optionally substituted with analkenyl or aralkyl. Another embodiment provides a compound of Formula(IV), wherein R⁴ is hydrogen, R¹ and R² are hydrogen, X is C₁-C₂alkylene, and Y is a phenyl optionally substituted with an alkoxy, anaralkoxy, or a cycloalkylalkoxy. Another embodiment provides a compoundof Formula (IV), wherein R⁴ is hydrogen, R¹ and R² are hydrogen, X isC₁-C₂ alkylene, and Y is a phenyl optionally substituted with an alkenylor aralkyl.

In some embodiments the carboxylic acid or ester group of thesubstituted pyrazolylpyridine derivative compound is replaced by acarboxylic acid bioisostere. One embodiment provides a compound ofFormula (VII) or a tautomer, stereoisomer, geometric isomer, N-oxide, orpharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl; Q is —C(O)N(H)CN, —C(O)N(H)OH, or    tetrazolyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides the compound of Formula (VII) wherein:

-   if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,    trifluoromethyl, isopropyl or cyclopropyl; or-   if R¹ and R³ are both hydrogen, then R² is not methyl,    trifluoromethyl, bromine or chlorine; or-   if R¹ and R³ are both methyl, then R² is not hydrogen, methyl or    ethyl.

Another embodiment provides a compound of Formula (VII), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (VII),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(VII), wherein R³ is hydroxy. Another embodiment provides a compound ofFormula (VII), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides acompound of Formula (VII), wherein R³ is aralkyl. Another embodimentprovides a compound of Formula (VII), wherein R³ is —OR⁵. Anotherembodiment provides a compound of Formula (VII), wherein —OR⁵ iscarbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.Another embodiment provides a compound of Formula (VII), wherein —OR⁵ isaralkyl, or heteroarylalkyl. Another embodiment provides a compound ofFormula (VII), wherein —OR⁵ is carbocyclylalkyl, or heterocyclylalkyl.Another embodiment provides a compound of Formula (VII), wherein R³ isaryl. Another embodiment provides a compound of Formula (VII), whereinR¹ and R² are both hydrogen. Another embodiment provides a compound ofFormula (VII), wherein R¹ is hydrogen. Another embodiment provides acompound of Formula (VII), wherein R² is hydrogen. Another embodimentprovides a compound of Formula (VII), wherein R¹ and R² are bothhydrogen. Another embodiment provides a compound of Formula (VII),wherein R³ is phenyl substituted by at least one substituent selectedfrom alkyl, halogen, hydroxy, alkoxy or alkylsulfone. Another embodimentprovides a compound of Formula (VII), wherein R³ is phenyl substitutedat the 4-position.

One embodiment provides a compound of Formula (VIII) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (VIII), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (VIII),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(VIII), wherein R¹ or R² is alkyl. Another embodiment provides acompound of Formula (VIII), wherein R¹ or R² is carbocyclyl. Anotherembodiment provides a compound of Formula (VIII), wherein R¹ or R² isaryl. Another embodiment provides a compound of Formula (VIII), whereinR¹ or R² is aralkyl.

One embodiment provides a compound of Formula (IX) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is C₂-C₁₀ alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (IX), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (IX),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(IX), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides a compoundof Formula (IX), wherein R³ is aryl. Another embodiment provides acompound of Formula (IX), wherein R³ is aralkyl.

One embodiment provides a compound of Formula (X) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

Another embodiment provides a compound of Formula (X), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (X), whereinR⁴ is alkyl. Another embodiment provides a compound of Formula (X),wherein R¹ and R² are hydrogen. Another embodiment provides a compoundof Formula (X), wherein X is C₁-C₄ alkylene. Another embodiment providesa compound of Formula (X), wherein X is C₁-C₂ alkylene. Anotherembodiment provides a compound of Formula (X), wherein X is C₁ alkylene.Another embodiment provides a compound of Formula (X), wherein Y ishydrogen. Another embodiment provides a compound of Formula (X), whereinY is carbocyclyl. Another embodiment provides a compound of Formula (X),wherein Y is aryl. Another embodiment provides a compound of Formula(X), wherein Y is phenyl. Another embodiment provides a compound ofFormula (X), wherein Y is heteroaryl.

Substituted Pyrazolylpyridazine Derivative Compounds

Substituted pyrazolylpyridazine derivative compounds are describedherein that inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic disease. The compounds described herein may,therefore, be useful for treating prostate cancer, breast cancer,bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (V) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (V), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (V), whereinR⁴ is alkyl. Another embodiment provides a compound of Formula (V),wherein R³ is hydroxy. Another embodiment provides a compound of Formula(V), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides a compoundof Formula (V), wherein R³ is aralkyl. Another embodiment provides acompound of Formula (V), wherein R³ is —OR⁵. Another embodiment providesa compound of Formula (V), wherein —OR⁵ is carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl. Another embodimentprovides a compound of Formula (V), wherein —OR⁵ is aralkyl, orheteroarylalkyl. Another embodiment provides a compound of Formula (V),wherein —OR⁵ is carbocyclylalkyl, or heterocyclylalkyl. Anotherembodiment provides a compound of Formula (V), wherein R³ is aryl.Another embodiment provides a compound of Formula (V), wherein R¹ and R²are both hydrogen. Another embodiment provides a compound of Formula(V), wherein R¹ is hydrogen. Another embodiment provides a compound ofFormula (V), wherein R² is hydrogen. Another embodiment provides acompound of Formula (V), wherein R¹ and R² are both hydrogen. Anotherembodiment provides a compound of Formula (V), wherein R³ is phenylsubstituted by at least one substituent selected from alkyl, halogen,hydroxy, alkoxy or alkylsulfone. Another embodiment provides a compoundof Formula (V), wherein R³ is phenyl substituted at the 4-position.

One embodiment provides a compound of Formula (XI) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   Q is —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (XI), wherein R⁴ ishydrogen. Another embodiment provides a compound of Formula (XI),wherein R⁴ is alkyl. Another embodiment provides a compound of Formula(XI), wherein R³ is hydroxy. Another embodiment provides a compound ofFormula (XI), wherein R³ is C₂-C₁₀ alkyl. Another embodiment provides acompound of Formula (XI), wherein R³ is aralkyl. Another embodimentprovides a compound of Formula (XI), wherein R³ is —OR⁵. Anotherembodiment provides a compound of Formula (XI), wherein —OR⁵ iscarbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl.Another embodiment provides a compound of Formula (XI), wherein —OR⁵ isaralkyl, or heteroarylalkyl. Another embodiment provides a compound ofFormula (XI), wherein —OR⁵ is carbocyclylalkyl, or heterocyclylalkyl.Another embodiment provides a compound of Formula (XI), wherein R³ isaryl. Another embodiment provides a compound of Formula (XI), wherein R¹and R² are both hydrogen. Another embodiment provides a compound ofFormula (XI), wherein R¹ is hydrogen. Another embodiment provides acompound of Formula (XI), wherein R² is hydrogen. Another embodimentprovides a compound of Formula (XI), wherein R¹ and R² are bothhydrogen. Another embodiment provides a compound of Formula (XI),wherein

-   R³ is phenyl substituted by at least one substituent selected from    alkyl, halogen, hydroxy, alkoxy or alkylsulfone. Another embodiment    provides a compound of Formula (XI), wherein R³ is phenyl    substituted at the 4-position.    Substituted Pyrazolylpyrimidine Derivative Compounds

Substituted pyrazolylpyrimidine derivative compounds are describedherein that inhibit a histone demethylase enzyme. These compounds, andcompositions comprising these compounds, are useful for the treatment ofcancer and neoplastic disease. The compounds described herein may,therefore, be useful for treating prostate cancer, breast cancer,bladder cancer, lung cancer and/or melanoma and the like.

One embodiment provides a compound of Formula (XII) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   Q is —CO₂R⁴, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; A is N and B    is CH; or A is CH and B is N; or A is C—OH and B is CH;-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   with the provision that R¹, R² and R³ are not all hydrogen.

Another embodiment provides a compound of Formula (XII), wherein A is Nand B is CH. Another embodiment provides a compound of Formula (XII),wherein A is CH and B is N. Another embodiment provides a compound ofFormula (XII), wherein A is C—OH and B is CH. Another embodimentprovides a compound of Formula (XII), wherein Q is —CO₂R⁴ and R⁴ ishydrogen. Another embodiment provides a compound of Formula (XII),wherein wherein Q is —CO₂R⁴ and R⁴ is alkyl. Another embodiment providesa compound of Formula (XII), wherein Q is —C(O)N(H)CN. Anotherembodiment provides a compound of Formula (XII), wherein Q is—C(O)N(H)OH. Another embodiment provides a compound of Formula (XII),wherein Q is tetrazolyl. Another embodiment provides a compound ofFormula (XII), wherein R³ is hydroxy. Another embodiment provides acompound of Formula (XII), wherein R³ is C₂-C₁₀ alkyl. Anotherembodiment provides a compound of Formula (XII), wherein R³ is aralkyl.Another embodiment provides a compound of Formula (XII), wherein R³ is—OR⁵. Another embodiment provides a compound of Formula (XII), wherein—OR⁵ is carbocyclylalkyl, heterocyclylalkyl, aralkyl, orheteroarylalkyl. Another embodiment provides a compound of Formula(XII), wherein —OR⁵ is aralkyl, or heteroarylalkyl. Another embodimentprovides a compound of Formula (XII), wherein —OR⁵ is carbocyclylalkyl,or heterocyclylalkyl. Another embodiment provides a compound of Formula(XII), wherein R³ is aryl. Another embodiment provides a compound ofFormula (XII), wherein R¹ and R² are both hydrogen. Another embodimentprovides a compound of Formula (XII), wherein R¹ is hydrogen. Anotherembodiment provides a compound of Formula (XII), wherein R² is hydrogen.Another embodiment provides a compound of Formula (XII), wherein R¹ andR² are both hydrogen. Another embodiment provides a compound of Formula(XII), wherein R³ is phenyl substituted by at least one substituentselected from alkyl, halogen, hydroxy, alkoxy or alkylsulfone. Anotherembodiment provides a compound of Formula (XII), wherein R³ is phenylsubstituted at the 4-position.

One embodiment provides a compound of Formula (XIII) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   Q is —CO₂R⁴, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; A is N and B    is CH; or A is CH and B is N; or A is C—OH and B is CH;-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

Another embodiment provides a compound of Formula (XIII), wherein A is Nand B is CH. Another embodiment provides a compound of Formula (XIII),wherein A is CH and B is N. Another embodiment provides a compound ofFormula (XIII), wherein A is C—OH and B is CH. Another embodimentprovides a compound of Formula (XIII), wherein Q is —CO₂R⁴ and R⁴ ishydrogen. Another embodiment provides a compound of Formula (XIII),wherein wherein Q is —CO₂R⁴ and R⁴ is alkyl. Another embodiment providesa compound of Formula (XIII), wherein Q is —C(O)N(H)CN. Anotherembodiment provides a compound of Formula (XIII), wherein Q is—C(O)N(H)OH. Another embodiment provides a compound of Formula (XIII),wherein Q is tetrazolyl. Another embodiment provides a compound ofFormula (XIII), wherein R⁴ is hydrogen. Another embodiment provides acompound of Formula (XIII), wherein R⁴ is alkyl. Another embodimentprovides a compound of Formula (XIII), wherein R¹ or R² is alkyl.Another embodiment provides a compound of Formula (XIII), wherein R¹ orR² is carbocyclyl. Another embodiment provides a compound of Formula(XIII), wherein R¹ or R² is aryl. Another embodiment provides a compoundof Formula (XIII), wherein R¹ or R² is aralkyl.

One embodiment provides a compound of Formula (XIV) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof,

-   wherein,-   Q is —CO₂R⁴, —C(O)N(H)CN, —C(O)N(H)OH, or tetrazolyl; A is N and B    is CH; or A is CH and B is N; or A is C—OH and B is CH;-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

Another embodiment provides a compound of Formula (XIV), wherein A is Nand B is CH. Another embodiment provides a compound of Formula (XIV),wherein A is CH and B is N. Another embodiment provides a compound ofFormula (XIV), wherein A is C—OH and B is CH. Another embodimentprovides a compound of Formula (XIV), wherein Q is —CO₂R⁴ and R⁴ ishydrogen. Another embodiment provides a compound of Formula (XIV),wherein wherein Q is —CO₂R⁴ and R⁴ is alkyl. Another embodiment providesa compound of Formula (XIV), wherein Q is —C(O)N(H)CN. Anotherembodiment provides a compound of Formula (XIV), wherein Q is—C(O)N(H)OH. Another embodiment provides a compound of Formula (XIV),wherein Q is tetrazolyl. Another embodiment provides a compound ofFormula (XIV), wherein R⁴ is hydrogen. Another embodiment provides acompound of Formula (XIV), wherein R⁴ is alkyl. Another embodimentprovides a compound of Formula (XIV), wherein R¹ and R² are hydrogen.Another embodiment provides a compound of Formula (XIV), wherein X isC₁-C₄ alkylene. Another embodiment provides a compound of Formula (XIV),wherein X is C₁-C₂ alkylene. Another embodiment provides a compound ofFormula (XIV), wherein X is C₁ alkylene. Another embodiment provides acompound of Formula (XIV), wherein Y is hydrogen. Another embodimentprovides a compound of Formula (XIV), wherein Y is carbocyclyl. Anotherembodiment provides a compound of Formula (XIV), wherein Y is aryl.Another embodiment provides a compound of Formula (XIV), wherein Y isphenyl. Another embodiment provides a compound of Formula (XIV), whereinY is heteroaryl.

In some embodiments, the substituted pyrazolylpyridine derivativecompound disclosed herein has the structure provided in Table 1.

TABLE 1 Chemical Synthesis Example Structure Name  1

2-(5-hydroxy-3-methyl-1H- pyrazol-1-yl)isonicotinic acid  2

2-(3-cyclopropyl-5-hydroxy-1H- pyrazol-1-yl)isonicotinic acid  3

2-(5-hydroxy-3,4- dimethyl-1H-pyrazol-1- yl)isonicotinic acid  4

2-(5-hydroxy-3-methyl-4- phenyl-1H-pyrazol-1- yl)isonicotinic acid  5

2-(3-(2-fluorophenyl)-5-hydroxy- 1H-pyrazol-1-yl)isonicotinic acid  6

2-(5-hydroxy-3-propyl-1H- pyrazol-1-yl)isonicotinic acid  7

2-(3-(2-chlorophenyl)-5-hydroxy- 1H-pyrazol-1-yl)isonicotinic acid  8

2-(3-benzyl-5-hydroxy-1H- pyrazol-1-yl)isonicotinic acid  9

2-(5-hydroxy-3-(methoxymethyl)- 1H-pyrazol-1-yl)isonicotinic acid 10

2-(5-hydroxy-3-(phenoxymethyl)- 1H-pyrazol-1-yl)isonicotinic acid 11

2-(5-hydroxy-1H-pyrazol-1- yl)isonicotinic acid 12

2-(5-p-tolyl-1H-pyrazol-1- yl)isonicotinic acid 13

2-(5-m-tolyl-1H-pyrazol-1- yl)isonicotinic acid 14

2-(5-(2,4-difluorophenyl)-1H- pyrazol-1-yl)isonicotinic acid 15

2-(5-(3,4-difluorophenyl)-1H- pyrazol-1-yl)isonicotinic acid 16

2-(5-(3-fluorophenyl)-1H-pyrazol- 1-yl)isonicotinic acid 17

2-(5-(3-hydroxyphenyl)-1H- pyrazol-1-yl)isonicotinic acid 18

2-(5-(4-hydroxyphenyl)-1H- pyrazol-1-yl)isonicotinic acid 19

2-(5-(4-(methylsulfonyl)phenyl)- 1H-pyrazol-1-yl)isonicotinic acid 20

2-(5-(3-methoxy-4-methylphenyl)- 1H-pyrazol-1-yl)isonicotinic acid 21

2-(5-(3-hydroxy-4-methylphenyl)- 1H-pyrazol-1-yl)isonicotinic acid 22

2-(5-(4-chloro-3-methoxyphenyl)- 1H-pyrazol-1-yl)isonicotinic acid 23

2-(5-(4-chloro-3-hydroxyphenyl)- 1H-pyrazol-1-yl)isonicotinic acid 24

2-[5-(1H-indazol-6-yl)-1H- pyrazol-1-yl]pyridine-4-carboxylic acid 25

methyl 2-[5-(1H-indazol-6-yl)-1H- pyrazol-1-yl]pyridine-4- carboxylate26

2-(5-phenyl-1H-pyrazol-1- yl)isonicotinic acid 27

2-(5-(4-fluorophenyl)-1H-pyrazol- 1-yl)isonicotinic acid 28

2-(5-(3-hydroxy-4- (methylsulfonyl)phenyl)-1H- pyrazol-1-yl)isonicotinicacid 29

2-(3-methyl-5-p-tolyl-1H-pyrazol- 1-yl)isonicotinic acid 30

2-(3-ethyl-5-p-tolyl-1H-pyrazol-1- yl)isonicotinic acid 31

2-(5-methyl-1H-pyrazol-1- yl)isonicotinic acid 32

2-(5-benzyl-1H-pyrazol-1- yl)isonicotinic acid 33

2-(3-benzyl-1H-pyrazol-1- yl)isonicotinic acid 34

2-(5-phenethyl-1H-pyrazol-1- yl)isonicotinic acid 35

2-(3-phenethyl-1H-pyrazol-1- yl)isonicotinic acid 36

2-(5-methyl-4-phenyl-1H-pyrazol- 1-yl)isonicotinic acid 37

2-(5-methoxy-3-methyl-1H- pyrazol-1-yl)isonicotinic acid 38

2-(5-(benzyloxy)-3-methyl-1H- pyrazol-1-yl)isonicotinic acid 39

2-(5-(benzyloxy)-1H-pyrazol-1- yl)isonicotinic acid 40

2-{5-[(4-fluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid41

2-{5-[(3-fluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid42

2-{5-[(3-methoxybenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid43

2-{5-[(4-methoxybenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid44

2-(5-butyl-1H-pyrazol-1- yl)isonicotinic acid 45

2-(3-butyl-1H-pyrazol-1- yl)pyridine-4-carboxylic acid 46

2-(5-(4-bromophenyl)-1H-pyrazol- 1-yl)isonicotinic acid 47

2-{5-[4-(dimethylamino)phenyl]- 1H-pyrazol-1-yl}pyridine-4- carboxylicacid 48

2-[3-amino-5-(4-methylphenyl)- 1H-pyrazol-1-yl]pyridine-4- carboxylicacid 49

2-[5-(1H-indazol-6-ylmethoxy)- 1H-pyrazol-1-yl]pyridine-4- carboxylicacid 50

2-{5-[(1-methyl-1H-indazol-6- yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 51

2-{5-[(1-methyl-1H-indazol-6- yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 52

2-{5-[(3,4- difluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylicacid 53

2-{5-[(4- chlorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid54

2-(5-{[4- (trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid 55

2-{5-[(4-methylbenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid56

2-{5-[(4-ethylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine- 4-carboxylic acid57

2-{5-[(4-bromobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid58

2-{5-[(3-chlorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid59

2-{5-[(2-fluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid60

2-[5-(pyridin-3-ylmethoxy)-1H- pyrazol-1-yl]pyridine-4-carboxylic acid61

2-[5-(pyridin-4-ylmethoxy)-1H- pyrazol-1-yl]pyridine-4-carboxylic acid62

methyl 2-{5-[(4- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 63

methyl 2-{5-[(3,4- difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 64

methyl 2-{5-[(4- chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 65

methyl 2-(5-{[4- (trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4- carboxylate 66

methyl 2-{5-[(4- methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 67

methyl 2-{5-[(4-ethylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate 68

methyl 2-{5-[(4- bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 69

methyl 2-[5-(benzyloxy)-1H- pyrazol-1-yl]pyridine-4- carboxylate 70

methyl 2-{5-[(3- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 71

2-{5-[(4,4- difluorocyclohexyl)methoxy]-1H- pyrazol-1-yl}pyridine-4-carboxylic acid 72

2-{5-[(3-bromobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid73

2-{5-[(3-hydroxybenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4- carboxylic acid74

2-{5-[(4-chloro-3- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 75

2-{5-[(4-chloro-2- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 76

2-{5-[(3-chloro-4- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 77

2-{5-[(4-cyclopropylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4- carboxylicacid 78

methyl 2-{5-[(4-chloro-3- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 79

methyl 2-{5-[(4-chloro-2- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 80

methyl 2-{5-[(3-chloro-4- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 81

methyl 2-{5-[(4- cyclopropylbenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4-carboxylate 82

2-[5-[1-(4- fluorophenyl)ethoxy]pyrazol-1- yl]pyridine-4-carboxylic acid83

2-[5-[(3,3- difluorocyclobutyl)methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 84

2-[5-[(4-fluorophenyl)methoxy]-4- methylpyrazol-1-yl]pyridine-4-carboxylic acid 85

2-[4-ethyl-5-[(4- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 86

2-[5-[(2,4- difluorophenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylicacid 87

2-[5-[(3,4- dichlorophenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylicacid 88

2-[5-[(2,4- dichlorophenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylicacid 89

2-[5-[(4-chloro-2- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 90

2-[5-[(4-chloro-2- methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 91

2-[5-[[4-chloro-3- (trifluoromethyl)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 92

2-[5-[(3-chloro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 93

2-[5-[(3-fluoro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 94

2-[5-[(2,3-difluoro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 95

2-[5-[(3-chloro-4- ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 96

2-[5-[(4-ethyl-3- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 97

2-[5-[(3- cyanophenyl)methoxy]pyrazol-1- yl]pyridine-4-carboxylic acid98

methyl 2-[5-[(4- cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 99

2-[5-[(4- cyanophenyl)methoxy]pyrazol-1- yl]pyridine-4-carboxylic acid100 

methyl 2-[5-[(3-chloro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 101 

methyl 2-[5-[(3-fluoro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 102 

methyl 2-[5-[(3-chloro-4- ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 103 

methyl 2-[5-[(2,3-difluoro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 104 

methyl 2-[5-[(4-ethyl-3- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 105 

2-[5-[(4-chloro-2- phenylmethoxyphenyl)methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 106 

2-[5-[[4-chloro-2- (cyclopropylmethoxy)phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 107 

2-[5-[(4-chloro-2- propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 108 

2-[5-[[4-chloro-2-(2,2,2- trifluoroethoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 109 

2-[5-[(4-fluorophenyl)methoxy]-4- (2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carboxylic acid 110 

2-[4-[2-(dimethylamino)ethyl]-5- [(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 111 

2-[5-[(2-butoxy-4- chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 112 

2-[5-[[4-chloro-2-(2- methylpropoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 113 

2-[5-[(4-chloro-2-propan-2- yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 114 

2-[5-[(2-butan-2-yloxy-4- chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 115 

2-[5-[(4-chloro-2- ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 116 

2-[5-[[4-chloro-2-(2- methoxyethoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 117 

2-[5-[[4-chloro-2-[(4- fluorophenyl)methoxy]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 118 

2-[5-[[4-fluoro-2-[(4- fluorophenyl)methoxy]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 119 

2-[5-[[4-fluoro-2-[(E)-2-(4- fluorophenyl)ethenyl]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 120 

2-[5-[[4-chloro-2-[(E)-2-(4- fluorophenyl)ethenyl]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 121 

2-[5-[[4-fluoro-2-[2-(4- fluorophenyl)ethyl]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 122 

2-[5-[[4-chloro-2-[2-(4- fluorophenyl)ethyl]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 123 

2-[5-(2,3-dihydro-1-benzofuran-7- ylmethoxy)pyrazol-1-yl]pyridine-4-carboxylic acid 124 

2-[5-[(2,2-dimethyl-3H-1- benzofuran-7-yl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 125 

2-[5-[(4-cyano-2- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 126 

2-[5-[(4-cyano-2- ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 127 

2-[5-[(4-chloro-2- ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 128 

2-[5-[(4-fluoro-2- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 129 

2-[5-[(2-ethyl-4- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 130 

2-[5-[(2-chloro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 131 

2-[5-[(2-fluoro-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 132 

2-[5-[(2,4- dimethylphenyl)methoxy]pyrazol- 1-yl]pyridine-4-carboxylicacid 133 

2-[5-[(2-methoxy-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 134 

2-[5-[(2-cyano-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 135 

2-[5-[(2-ethyl-4- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 136 

2-[5-[[4-chloro-2-(1- phenylethoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 137 

2-[5-[[4-fluoro-2-(1- phenylethoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 138 

2-[5-[[4-chloro-3-[(4- fluorophenyl)methoxy]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 139 

2-[5-[[4-fluoro-3-[(4- fluorophenyl)methoxy]phenyl]-methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 140 

2-[5-[[4-chloro-3- (cyclopropylmethoxy)phenyl]-mrthoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 141 

2-[5-[[4-chloro-3-(2,2,2- trifluoroethoxy)phenyl]methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 142 

2-[5-[(4-bromo-2- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 143 

2-[5-[(4-bromo-2- methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 144 

2-[5-[(4-iodo-2- methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 145 

2-[5-[(4-iodo-2- methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 146 

2-[5-[(5-fluoro-2,3-dihydro-1H- indcn-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylic acid 147 

2-[5-[(5-chloro-2,3-dihydro-1H- inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylic acid 148 

2-[5-[(6-fluoro-1,2,3,4- tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4- carboxylic acid 149 

2-[5-[(6-chloro-1,2,3,4- tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4- carboxylic acid 150 

2-[5-[(2-chloro-4- ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 151 

2-[5-[(4-ethyl-2- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 152 

2-[5-[(2-chloro-4- cyclopropylphenyl)methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 153 

2-[5-[(4-cyclopropyl-2- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 154 

2-[5-[(3-chloro-4- cyclopropylphenyl)methoxy]-pyrazol-1-yl]pyridine-4-carboxylic acid 155 

2-[5-[(4-cyclopropyl-3- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 156 

2-[4-[2-[(4-fluorophenyl)methyl- methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylic acid 157 

N-cyano-2-[4-[2-[(4- fluorophenyl)methyl- methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxamide 158 

2-[3-(4-chlorophenyl)-5- hydroxypyrazol-1-yl]pyridine-4- carboxylic acid159  

2-[3-(3-chlorophenyl)-5- hydroxypyrazol-1-yl]pyridine-4- carboxylic acid160 

2-(3-cyclopentyl-5- hydroxypyrazol-1-yl)pyridine-4- carboxylic acid 161 

2-[3-[(2,6-difluorophenyl)methyl]- 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 162 

2-[5-hydroxy-3-(1- phenylethyl)pyrazol-1-yl]pyridine- 4-carboxylic acid163 

2-[3-[(2-chlorophenyl)methyl]-5- hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 164 

2-[3-[(3-chlorophenyl)methyl]-5- hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 165 

2-[3-[(4-chlorophenyl)methyl]-5- hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 166 

5-(1-phenylethyl)-2-[4-(1H- tetrazol-5-yl)pyridin-2-yl]pyrazol- 3-ol167 

5-[(2-chlorophenyl)methyl]-2-[4- (1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 168 

5-[(3-chlorophenyl)methyl]-2-[4- (1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 169 

5-[(4-chlorophenyl)methyl]-2-[4- (1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 170 

2-[3-[2-(4-chlorophenyl)propan-2- yl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 171 

2-[3-[1-(4- chlorophenyl)cyclopropyl]-5- hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 172 

2-[3-[(3,5- dichlorophenyl)methyl]-5- hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 173 

2-[3-[(4-fluoro-2- methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4- carboxylic acid 174 

2-[3-[(2-fluoro-4- methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4- carboxylic acid 175 

2-[3-[(2,4-difluorophenyl)methyl]- 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid

In additional embodiments, the substituted pyrazolylpyridine derivativecompound disclosed herein is selected from a compound of Table 2.

TABLE 2

2-(5-{[1-(4- fluorophenyl)cyclopropyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-(5-{[1-(4-chlorophenyl)cyclopropyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-{5-[(1R)-1-(4-fluorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-1-(4-fluorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-(5-{[2-(4-fluorophenyl)propan-2- yl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-{5-[(1R)-1-(4-fluorophenyl)propoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1R)-1-(4-chlorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-1-(4-chlorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-(5-{[2-(4-chlorophenyl)propan-2-yl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-{5-[(1R)-1-(4-chlorophenyl)propoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-1-(4-fluorophenyl)propoxy]-lH-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1R)-2-cyclopropyl-1-(4- fluorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-2-cyclopropyl-1-(4- fluorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-methyl-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-1-(4-chlorophenyl)propoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1R)-2-cyclopropyl-1-(4- chlorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(1S)-2-cyclopropyl-1-(4- chlorophenyl)ethoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{4-ethyl-5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{4-cyclopropyl-5-[(4- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{4-(cyclopropylmethyl)-5-[(4- fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-fluorobenzyl)oxy]-4-propyl-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{3-fluoro-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-cyclopropyl-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{4-(cyclopropylmethyl)-5-[(4- chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-propyl-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{3-fluoro-5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-[5-[[4-fluoro-2-(2- methylpropoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-{5-[(7-fluoro-2,3-dihydro-1- benzofuran-4-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4- carboxylic acid

2-(5-{[4-fluoro-2- (trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-(5-{[4-fluoro-3- (trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-{5-[(7-chloro-2,3-dihydro-1-benzofuran- 4-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-(5-{[4-chloro-2- (trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-(2- hydroxyethyl)-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-cyano-2-fluorobenzyl)oxy]-1H- pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-fluorobenzyl)oxy]-4-[2- (methylamino)ethyl]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chloro-2,6-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-[2- (dimethylamino)ethyl]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-{5-[(4-chlorobenzyl)oxy]-4-[2- (methylamino)ethyl]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

2-(5-(4-fluorobenzyloxy)-4-(2-((2- hydroxyethyl)(methyl)amino)ethyl)-1H-pyrazol-1-yl)isonicotinic acid

2-(4-(2-(2-(dimethylamino)ethoxy)ethyl)- 5-(4-fluorobenzyloxy)-1H-pyrazol-1-yl)isonicotinic acid

2-(4-(3-(dimethylamino)propyl)-5-(4- fluorobenzyloxy)-1H-pyrazol-1-yl)isonicotinic acid

2-(5-(4-chlorobenzyloxy)-4-(2-((2- hydroxyethyl)(methyl)amino)ethyl)-1H-pyrazol-1-yl)isonicotinic acid

2-(5-(4-chlorobenzyloxy)-4-(2-(2- (dimethylamino)ethoxy)ethyl)-1H-pyrazol-1-yl)isonicotinic acid

2-(5-(4-chlorobenzyloxy)-4-(3- (dimethylamino)propyl)-1H-pyrazol-1-yl)isonicotinic acid

2-[5-[(4-fluorophenyl)methoxy]-4-(2- pyrrolidin-1-ylethyl)pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[(4-fluoro-2- methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[(2-ethoxy-4- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[[4-fluoro-2-(2,2,2- trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid

2-[5-[(4-chlorophenyl)methoxy]-4-(2-pyrrolidin-1-ylethyl)pyrazol-1-yl]pyridine- 4-carboxylic acid

2-[5-[(4-fluoro-2- propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[(2-butoxy-4- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[[2-(cyclopropylmethoxy)-4- fluorophenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[(4-fluoro-2-propan-2- yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

2-[5-[(2-butan-2-yloxy-4- fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acidPreparation of the Substituted Pyrazolylpyridine, Pyrazolylpyridazine,and Pyrazolylpyrimidine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Suitable reference books andtreatise that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, include for example, “SyntheticOrganic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler etal., “Organic Functional Group Preparations,” 2nd Ed., Academic Press,New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist,“Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J.March, “Advanced Organic Chemistry: Reactions, Mechanisms andStructure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants may also be identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the substituted pyrazolylpyridine derivativecompounds described herein is P. H. Stahl & C. G. Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The substituted pyrazolylpyridine and pyrazolylpyridazine derivativecompounds are prepared by the general synthetic routes described belowin Schemes 1-8.

One method for preparing compounds such as compound 1-2 is provided inScheme 1. 2-Chloroisonicotinic acid or 6-chloropyridazine-4-carboxylicacid are treated with hydrazine hydrate in an organic solvent, such as1,4-dioxane, under reflux conditions (e.g., about 100° C.) to giveintermediates 1-1. Subsequent reaction with substituted acetoacetylester in AcOH under heating conditions affords compound s1-2.

A method for preparing compounds such as compounds 2-3 is provided inScheme 2. 2-Chloroisonicotinonitrile or6-chloropyridazine-4-carbonitrile are treated with hydrazine hydrate ina mixture of an alcoholic solvent (such as 1-butanol) and an organicsolvent (such as THF) at elevated temperature (e.g. about 60-100° C.) togive intermediates 2-1. Subsequent reaction with an acetoacetyl ester ina mixture of an alcoholic solvent (such as ethanol) heated to reflux inpresence of acetic acid provides cyclized hydroxypyrazole pyridineintermediates 2-2. Hydrolysis using concentrated sodium hydroxidesolution (such as 5-10 N) in ethanol provides the acids 2-3.

Two methods of preparing acetoacetyl esters are provided in Scheme 3. Inthe first method, a substituted acetophenone is treated with diethylcarbonate and sodium hydride in an organic solvent such as THF to giveketoester 3-2. In the second method, an acetyl chloride can is reactedwith 2,2-dimethyl-1,3-dioxane-4,6-dione in presence of a base, such aspyridine, in an organic solvent, such as DCM, to give intermediate 3-3.Ketoesters such as 3-2 and 3-3 are condensed with2-hydrazinylisonicotinonitrile, 6-hydrazinylpyridazine-4-carbonitrile,2-hydrazinylpyrimidine-4-carbonitrile or6-hydrazinylpyrimidine-4-carbonitrile to generate hydroxypyrazolepyridine, hydroxypyrazole pyridazine, and hydroxypyrazole pyrimidineanalogs.

A method for preparing compounds such as compounds 4-3 is provided inScheme 4. Substituted acetophenones are reacted with either DMF-DMA or(1,1-dimethoxy-ethyl)-dimethylamine under heating conditions (e.g. about100-120° C.) to give intermediate 4-1. Subsequent cyclization with2-hydrazylisonicotinonitrile or 6-hydrazinylpyridazine-4-carbonitrile,either as free bases or hydrochloride salts, in an alcohol solvent suchas 2-methoxyethanol (if hydrochloride salt is used), or ethanol in thepresence of acetic acid (if the free bases of compounds 2-1 are used)under heating conditions provides intermediates 4-2. Hydrolysis of thenitrile group using concentrated sodium hydroxide solution (5-10 M) inethanol with heat affords the acid products 4-3.

A method for preparing compounds such as compounds 5-3 is provided inScheme 5. Cyclization of 2-hydrazinylisoniconinonitrile or6-hydrazinylpyridazine-4-carbonitrile with ethyl 3-oxobutanoate in analcoholic solvent, such as ethanol, in presence of acetic acid providesintermediates 5-1. Alkylation of the hydroxyl group using an alkylhalide, such as alkyl bromide or alkyl iodide, in an organic solvent,such as DMF, in the presence of a base, e.g. K₂CO₃, gives products 5-2.Subsequent hydrolysis using concentrated NaOH in alcohol provides theacid products 5-3.

A method to prepare compounds such as compound 6-4 and 6-5 is providedin Scheme 6. 2-Hydrazinyl-isonicotinonitrile or6-hydrazinylpyridazine-4-carbonitrile react with ethyl(2E)-3-(dimethylamino)prop-2-enoate in ethanol in the presence of aceticacid to give intermediates 6-1. Upon treatment with a strong base, suchas potassium t-butoxide, the hydroxypyrazole intermediates 6-2 isobtained. A Mitsunobu reaction, wherein intermediates 6-2 are treatedwith an alcohol, an azadicarboxylate, such as DIAD, a ligand, such astriphenylphosphine, in an organic solvent, such as THF, gives a mixtureof O-alkylation and N-alkylation products. Separation via flash columnchromatography provides the desired O-alkylation products 6-3, which arethen hydrolyzed to the acids 6-4. The acids are then treated with excessdiazomethane (e.g. 10 equiv.) in an organic solvent such as THF to givethe methyl esters, compounds 6-5.

Methods for preparing compounds of formula 7-2 and 7-3 are provided inScheme 7. Treatment of acids 7-1 with hydroxylamine hydrochloride in thepresence of a coupling reagent, such as HATU, in a solvent, such as DMF,at room temperature for 1 to 24 hours provides compounds 7-2. Compounds7-1 can also be used to prepare N-acylcyanamides such as compound 7-3.Treatment of 7-1 with cyanamide in the presence of an acid couplingreagent, such as HATU, in a solvent, such as DMF, at room temperaturefor 1 to 24 hours provides compounds 7-3.

A method for preparing compounds of formula 8-2 is provided in Scheme 8.Treatment of the nitrile intermediates 8-1 with sodium azide andammonium chloride in DMF followed by heating to 90° C. for 2 to 24 hoursprovides the desired tetrazole derivatives 8-2.

The substituted pyrazolylpyrimidine derivative compounds are prepared bythe general synthetic routes described below in Schemes 9-15.

One method for preparing compounds such as compounds 9-2 is provided inScheme 9. 6-Chloropyrimidine-4-carboxylic acid or2-chloropyrimidine-4-carboxylic acid are treated with hydrazine hydratein an organic solvent, such as 1,4-dioxane, under reflux conditions(e.g., about 100° C.) to give intermediates 9-1. Subsequent reactionwith substituted acetoacetyl ester in AcOH under heating conditionsaffords compounds 9-2.

A method for preparing compounds such as compounds 10-3 is provided inScheme 10. 2-Chloropyrimidine-4-carbonitrile or6-chloropyrimidine-4-carbonitrile are treated with hydrazine hydrate ina mixture of an alcoholic solvent (such as 1-butanol) and an organicsolvent (such as THF) at elevated temperature (e.g. about 60-100° C.) togive intermediates 10-1. Subsequent reaction with an acetoacetyl esterin a mixture of an alcoholic solvent (such as ethanol) heated to refluxin presence of acetic acid provides cyclized hydroxypyrazole pyridineintermediates 10-2. Hydrolysis using concentrated sodium hydroxidesolution (such as 5-10 N) in ethanol provides the acids 10-3.

A method for preparing compounds such as compounds 11-3 is provided inScheme 11. Cyclization of 2-hydrazinylpyrimidine-4-carbonitrile or6-hydrazinylpyrimidine-4-carbonitrile either as free base orhydrochloride salts with intermediate 4-1, in an alcohol solvent such as2-methoxyethanol (if hydrochloride salts are used), or ethanol in thepresence of acetic acid (if the free base of compounds 10-1 are used)under heating conditions provides intermediates 11-2. Hydrolysis of thenitrile group using concentrated sodium hydroxide solution (5-10 M) inethanol with heat affords the acid products 11-3.

A method for preparing compounds such as compounds 12-3 is provided inScheme 12. Cyclization of 2-hydrazinylpyrimidine-4-carbonitrile or6-hydrazinylpyrimidine-4-carbonitrile with ethyl 3-oxobutanoate in analcoholic solvent, such as ethanol, in presence of acetic acid providesintermediates 12-1. Alkylation of the hydroxyl group using an alkylhalide, such as alkyl bromide or alkyl iodide, in an organic solvent,such as DMF, in the presence of a base, e.g. K₂CO₃, gives products 12-2.Subsequent hydrolysis using concentrated NaOH in alcohol provides theacid products 12-3.

A method to prepare compounds such as compounds 13-4 or 13-5 is providedin Scheme 13. 2-Hydrazinylpyrimidine-4-carbonitrile or6-hydrazinylpyrimidine-4-carbonitrile react with ethyl(2E)-3-(dimethylamino)prop-2-enoate in ethanol in the presence of aceticacid to give intermediates 13-1. Upon treatment with a strong base, suchas potassium t-butoxide, the hydroxypyrazole intermediates 13-2 areobtained. A Mitsunobu reaction, wherein intermediates 13-2 are treatedwith an alcohol, an azadicarboxylate, such as DIAD, a ligand, such astriphenylphosphine, in an organic solvent, such as THF, gives a mixtureof O-alkylation and N-alkylation products. Separation via flash columnchromatography provides the desired O-alkylation products 13-3, which isthen hydrolyzed to the acids 13-4. The acids are then treated withexcess diazomethane (e.g. 10 equiv.) in an organic solvent such as THFto give the methyl esters, compounds 13-5.

Methods for preparing compounds of formula 14-2 and 14-3 are provided inScheme 14. Treatment of acids 14-1 with hydroxylamine hydrochloride inthe presence of a coupling reagent, such as HATU, in a solvent, such asDMF, at room temperature for 1 to 24 hours provides compounds 14-2.Compounds 14-1 can also be used to prepare N-acylcyanamides such ascompounds 14-3. Treatment of 14-1 with cyanamide in the presence of anacid coupling reagent, such as HATU, in a solvent, such as DMF, at roomtemperature for 1 to 24 hours provides compounds 14-3.

A method for preparing compounds of formula 15-2 is provided in Scheme15. Treatment of the nitrile intermediates 15-1 with sodium azide andammonium chloride in DMF followed by heating to 90° C. for 2 to 24 hoursprovides the desired tetrazole derivatives 15-2.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Histone Demethylase

Chromatin is the complex of DNA and protein that makes up chromosomes.Histones are the major protein component of chromatin, acting as spoolsaround which DNA winds. Changes in chromatin structure are affected bycovalent modifications of histone proteins and by non-histone bindingproteins. Several classes of enzymes are known which can covalentlymodify histones at various sites.

Proteins can be post-translationally modified by methylation on aminogroups of lysines and guanidino groups of arginines or carboxymethylatedon aspartate, glutamate, or on the C-terminus of the protein.Post-translational protein methylation has been implicated in a varietyof cellular processes such as RNA processing, receptor mediatedsignaling, and cellular differentiation. Post-translational proteinmethylation is widely known to occur on histones, such reactions knownto be catalyzed by histone methyltransferases, which transfer methylgroups from S-adenyosyl methionine (SAM) to histones. Histonemethylation is known to participate in a diverse range of biologicalprocesses including heterochromatin formation, X-chromosomeinactivation, and transcriptional regulation (Lachner et al., (2003) J.Cell Sci. 116:2117-2124; Margueron et al., (2005) Curr. Opin. Genet.Dev. 15:163-176).

Unlike acetylation, which generally correlates with transcriptionalactivation, whether histone methylation leads to transcriptionactivation or repression depends on the particular site of methylationand the degree of methylation (e.g., whether a particular histone lysineresidue is mono-, di-, or tri-methylated). However, generally,methylation on H3K9, H3K27 and H4K20 is linked to gene silencing, whilemethylation on H3K4, H3K36, and H3K79 is generally associated withactive gene expression. In addition, tri- and di-methylation of H3K4generally marks the transcriptional start sites of actively transcribedgenes, whereas mono-methylation of H3K4 is associated with enhancersequences.

A “demethylase” or “protein demethylase,” as referred to herein, refersto an enzyme that removes at least one methyl group from an amino acidside chain. Some demethylases act on histones, e.g., act as a histone H3or H4 demethylase. For example, an H3 demethylase may demethylate one ormore of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4demethylase may demethylate histone H4K20. Demethylases are known todemethylate either a mono-, di- and/or a tri-methylated substrate.Further, histone demethylases can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate and/oran oligonucleosome substrate, peptide substrate and/or chromatin (e.g.,in a cell-based assay).

The first lysine demethylase discovered was lysine specific demethylase1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 orH3K9, using flavin as a cofactor. A second class of Jumonji C (JmjC)domain containing histone demthylases were predicted, and confirmed whena H3K36 demethylase was found using a formaldehyde release assay, whichwas named JmjC domain containing histone demethylase 1 (JHDM1/KDM2A).

More JmjC domain-containing proteins were subsequently identified andthey can be phylogenetically clustered into seven subfamilies: JHDM1,JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 family of proteins are a family of histone-demethylases knownto demethylate tri- and di-methylated H3-K9, and were the firstidentified histone tri-methyl demethylases. In particular, ectopicexpression of JMJD2 family members was found to dramatically decreaselevels of tri- and di-methylated H3-K9, while increasing levels ofmono-methylated H3-K9, which delocalized Heterochromatin Protein 1 (HP1)and reduced overall levels of heterochromatin in vivo. Members of theJMJD2 subfamily of jumonji proteins include JMJD2C and its homologuesJMJD2A, JMJD2B, JMJD2D and JMJD2E. Common structural features found inthe JMJD2 subfamily of Jumonji proteins include the JmjN, JmjC, PHD andTdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylatetri-methylated H3K9 and H3K36. Histone demethylation by JMJD2C occursvia a hydroxylation reaction dependent on iron and α-ketoglutarate.,wherein oxidative decarboxylation of α-ketoglutarate by JMJD2C producescarbon dioxide, succinate, and ferryl and ferryl subsequentlyhydroxylates a methyl group of lysine H3K9, releasing formaldehyde.JMJD2C is known to modulate regulation of adipogenesis by the nuclearreceptor PPARy and is known to be involved in regulation of self-renewalin embryonic stem cells.

JARID Family

As used herein, a “JARID protein” includes proteins in the JARID1subfamily (e.g., JARID1A, JARID1B, JARID1C and JARID1D proteins) and theJARID2 subfamily, as well as homologues thereof. A further descriptionand listing of JARID proteins can be found in Klose et al. (2006) NatureReviews/Genetics 7:715-727. The JARID1 family contains several conserveddomains: JmjN, ARID, JmjC, PHD and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was initially found as a bindingpartner of retinoblastoma (Rb) protein. JARID1A was subsequently foundto function as a demethylase of tri- and di-methylated H3K4, and hasbeen found to promote cell growth, while inhibiting senescence anddifferentiation. For instance, abrogation of JARID1A from mouse cellsinhibits cell growth, induces senescence and differentiation, and causesloss of pluripotency of embryonic stem cells in vitro. JARID1A has beenfound to be overexpressed in gastric cancer and the loss of JARID1A hasbeen found to reduce tumorigenesis in a mouse cancer model.Additionally, studies have demonstrated that loss of the retinoblastomebinding protein 2 (RBP2) histone demethylase suppresses tumorigenesis inmice lacking Rb1 or Men1 (Lin et al. Proc. Natl. Acad. Sci. USA, Aug.16, 2011, 108(33), 13379-86; doi: 10.1073/pnas.1110104108) and theauthors of the study concluded that RBP2-inhibitory drugs would haveanti-cancer activity.

JARID1B, also referred to as KDM5B and PLU1, was originally found inexperiments to discover genes regulated by the HER2 tyrosine kinase.JARID1B has consistently been found to be expressed in breast cancercell lines, although restriction of JARID1B has been found in normaladult tissues, with the exception of the testis. In addition, 90% ofinvasive ductal carcinomas have been found to express JARID1B. Inaddition, JARID1B has been found to be up-regulated in prostate cancers,while having more limited expression in benign prostate, and has alsobeen found to be up-regulated in bladder cancer and lung cancer (bothSCLC and NSCLC). JARID1B has also been found to repress tumor suppressorgenes such as BRCA1, CAVI and 14-3-3σ, and knockdown of JARID1B wasfound to increase the levels of tri-methylated H3K4 at these genes.

FBXL10 and FBXL11

F-box and leucine-rich repeat protein 10 (FBXL10) and F-box andleucine-rich repeat protein 11 (FBXL11) are multifunctional F-box familyproteins that demethylate histone H3 through a hydroxylation basedmechanism. FBXL10, also known as lysine (K)-specific demethylase 2B(KDM2B) or Jumonji C domain-containing histone demethylase 1B (JHDM1B),preferentially demethylates trimethylated K4 and dimethylated K36 ofhistone H3, but contains weak or no activity for mono- andtri-methylated H3-K36. FBXL10 contains three domains, a catalytic JMJCdomain, an F-box domain and a COX DNA-binding domain. The N-terminalJMJC domain coordinates iron and α-ketoglutarate to catalyzedemethylation through the hydroxylation based mechanism. The CXXCDNA-binding domain allows FBXL10 to preferentially bind to transcribedregion of the ribosomal RNA, leading to repression of the ribosomal RNAgene transcription and ultimately leading to inhibition of cell growthand proliferation. FBXL10 has been found to be overexpressed in acutemyeloid leukemia, bladder carcinoma and pancreatic ductaladenocarcinoma. Recently, it has been demonstrated that FBXL10 regulatesthe expression of Polycomb target genes, those proteins are epigeneticregulators essential for stem cell differentiation. This regulationimplicates FBXL10's involvement in tumorigenesis through the regulationof these Polycomb target genes.

FBXL11, also known as KDM2A or JHDM1A, demethylates mono- anddi-methylated K36 of histone H3. The CXXC DNA-binding domain recognizesnon-methylated DNA and targets CpG island regions where it specificallyremoves H3K3 methylation. Further, FBXL11 is required to maintain aheterochromatic state, sustain centromeric integrity and genomicstability during mitosis. In addition, FBXL11 is a key negativeregulator of NF-KB. Overexpression of FBXL11 has been observed innon-small cell lung cancer (NSCLC) where FBXL11 upregulatesphosphor-ERK1/2 by repressing DUSP3 expression in NSCLC cell lines.Negative regulation of gluconeogenic gene expression by FBXL11 resultsin suppression of two rate-limiting gluconeogenic enzymes, critical formaintaining blood glucose homeostasis.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (I) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   with the provision:-   if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,    trifluoromethyl, isopropyl or cyclopropyl; or-   if R¹ and R³ are both hydrogen, then R² is not methyl, or    trifluoromethyl; or-   if R¹ and R³ are both methyl, then R² is not hydrogen, methyl or    ethyl; or-   if R¹ and R² are hydrogen, then R³ is not

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (II) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (III) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is C₂-C₁₀ alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (IV) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (V) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (VI) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for inhibiting ahistone-demethylase enzyme comprising contacting a histone demethylaseenzyme with a compound of Formula (VII)-(XIV) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof

In an additional embodiment is the method for inhibiting ahistone-demethylase enzyme, wherein the histone-demethylase enzymecomprises a JmjC domain. In an additional embodiment is the method forinhibiting a histone-demethylase enzyme, wherein the histone-demethylaseenzyme is selected from JARID1A, JARID1B, JMJD2C, JMJD2A, or FBXL10.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, in particular embodiments, the invention provides a methodof treating a disease regulated by histone methylation and/ordemethylation in a subject in need thereof by modulating the activity ofa demethylase comprising a JmjC domain (e.g., a histone demethylase suchas a JHDM protein(s)).

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (I) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   with the provision:-   if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,    trifluoromethyl, isopropyl or cyclopropyl; or-   if R¹ and R³ are both hydrogen, then R² is not methyl, or    trifluoromethyl; or-   if R¹ and R³ are both methyl, then R² is not hydrogen, methyl or    ethyl; or-   if R¹ and R² are hydrogen, then R³ is not

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (II) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (III) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is C₂-C₁₀ alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,    carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (IV) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is —O—X—Y;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl;-   X is C₁-C₈ alkylene or

where n is 0 to 4; and

-   Y is hydrogen, carbocyclyl, aryl, or heteroaryl.

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (V) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl; and-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (VI) or a tautomer, stereoisomer,geometric isomer, N-oxide, or pharmaceutically acceptable salt thereof,

-   wherein,-   R¹ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R³ is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl,    heterocyclyl, aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl,    aralkyl, or heteroarylalkyl;-   R⁴ is hydrogen or alkyl;-   each R⁵ is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,    aryl, heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, or    heteroarylalkyl.

In a further embodiment is the method for treating cancer in a subjectwherein the cancer is selected from prostate cancer, breast cancer,bladder cancer, lung cancer or melanoma.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (II), (III), (IV), (V), or (VI) or a pharmaceuticallyacceptable salt thereof, wherein the tumor is characterized by a loss ofretinoblastoma gene (RB1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, wherein the tumor is characterized by a loss ofmultiple endocrine neoplasia type 1 gene (Men1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (VII)-(XIV) or a pharmaceutically acceptable salt thereof,wherein the tumor is characterized by a loss of retinoblastoma gene(RB1) function.

In an additional embodiment is a method for inhibiting the growth of atumor comprising administering a composition comprising a compound ofFormula (VII)-(XIV), or a pharmaceutically acceptable salt thereof,wherein the tumor is characterized by a loss of multiple endocrineneoplasia type 1 gene (Men1) function.

In an additional embodiment is a method for treating cancer in subjectcomprising administering to the subject in need thereof a compositioncomprising a compound of Formula (VII)-(XIV) or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt thereof. In a further embodiment is the method for treating cancerin a subject wherein the cancer is selected from prostate cancer, breastcancer, bladder cancer, lung cancer or melanoma.

Pharmaceutical Compositions

In certain embodiments, a substituted pyrazolylpyridine,pyrazolylpyridazine, or pyrazolylpyrimidine derivative compound asdescribed herein is administered as a pure chemical. In otherembodiments, the substituted pyrazolylpyridine, pyrazolylpyridazine, orpyrazolylpyrimidine derivative compound as described is combined with apharmaceutically suitable or acceptable carrier (also referred to hereinas a pharmaceutically suitable (or acceptable) excipient,physiologically suitable (or acceptable) excipient, or physiologicallysuitable (or acceptable) carrier) selected on the basis of a chosenroute of administration and standard pharmaceutical practice asdescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)), thedisclosure of which is hereby incorporated herein by reference, in itsentirety.

Accordingly, provided herein is a pharmaceutical composition comprisingat least one substituted pyrazolylpyridine derivative compound, or astereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, or N-oxide thereof, together with one or more pharmaceuticallyacceptable carriers and, optionally, other therapeutic and/orprophylactic ingredients. Also provided herein is a pharmaceuticalcomposition comprising at least one substituted pyrazolylpyridazinederivative compound, or a stereoisomer, prodrug, pharmaceuticallyacceptable salt, hydrate, solvate, or N-oxide thereof, together with oneor more pharmaceutically acceptable carriers and, optionally, othertherapeutic and/or prophylactic ingredients. Further provided herein isa pharmaceutical composition comprising at least one substitutedpyrazolylpyrimidine derivative compound, or a stereoisomer, prodrug,pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof,together with one or more pharmaceutically acceptable carriers and,optionally, other therapeutic and/or prophylactic ingredients. Thecarrier(s) (or excipient(s)) is acceptable or suitable if the carrier iscompatible with the other ingredients of the composition and notdeleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formulas (I)-(V)or a tautomer, stereoisomer, geometric isomer, N-oxide, orpharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formulas(VII)-(XIV) or a tautomer, stereoisomer, geometric isomer, N-oxide, orpharmaceutically acceptable salt thereof.

In certain embodiments, the substituted pyrazolylpyridine derivativecompound as described by Formulas (I)-(V) is substantially pure, in thatit contains less than about 5%, or less than about 1%, or less thanabout 0.1%, of other organic small molecules, such as contaminatingintermediates or by-products that are created, for example, in one ormore of the steps of a synthesis method. In certain embodiments, thecompound as described by Formulas (VII)-(XIV) is substantially pure, inthat it contains less than about 5%, or less than about 1%, or less thanabout 0.1%, of other organic small molecules, such as contaminatingintermediates or by-products that are created, for example, in one ormore of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract.Suitable nontoxic solid carriers can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. (See, e.g., Remington: The Science and Practiceof Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedpyrazolylpyridine derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors that a personskilled in the medical art will use to determine dose.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

Oral doses can typically range from about 1.0 mg to about 1000 mg, oneto four times, or more, per day.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Preparation 1 2-Hydrazinylpyridine-4-carboxylic acid

To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol)in 1,4-dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol)dropwise at rt. The reaction mixture was heated at 100° C. overnight.The mixture was concentrated, and the residue was purified by flashcolumn chromatography (CH₂Cl₂/MeOH=20/1) to afford the title compound(650 mg, 42%) as a white solid. [M+H] Calc'd for C₆H₇N₃O₂, 154. Found,154.

Example 1 2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)isonicotinic acid

A mixture of 2-hydrazinylpyridine-4-carboxylic acid (306 mg, 2 mmol,PREPARATION 1) and ethyl 3-oxobutanoate (390 mg, 3 mmol) in AcOH (5 mL)was stirred at 100° C. overnight. The reaction mixture was cooled,concentrated, and purified by prep-HPLC to afford the title compound (72mg, 16%) as yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 2.72 (3H, s), 4.86(1H, s), 7.71 (1H, d, J=4.8 Hz), 8.55 (1H, d J=4.8 Hz), 8.81 (1H, s).[M+H] Calc'd for C₁₀H₉N₃O₃, 220. Found, 220.

Example 2 2-(3-cyclopropyl-5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 24% yield from2-hydrazinylpyridine-4-carboxylic acid and ethyl3-cyclopropyl-3-oxopropanoate according to the procedure for thepreparation of Example 1. ¹H NMR (400 MHz, CD₃OD): δ 0.83-0.88 (2H, m),1.05-1.09 (2H, m), 1.88-1.91 (1H, m), 4.86 (1H, s), 7.70 (1H, dd, J=5.2,1.2 Hz), 8.54 (1H, d, J=5.2 Hz), 8.75 (1H, s). [M+H] Calc'd forC₁₂H₁₁N₃O₃, 246. Found, 246.

Preparation 2 2-Hydrazinylpyridine-4-carbonitrile

To a solution of 2-chloropyridine-4-carbonitrile (20.0 g, 144 mmol) in1-butanol (150 mL) was added 1 M solution of hydrazine hydrate in THF(303 mL, 303 mmol) dropwise at rt. It was then heated at 60° C.overnight. The mixture was concentrated, and the residue was purified byflash column chromatography (CH₂Cl₂/MeOH=20/1) to afford the titlecompound (3.5 g, 18%) as a white solid. [M+H] Calc'd for C₆H₆N₄, 135.Found, 135.

Example 3 2-(5-Hydroxy-3,4-dimethyl-1H-pyrazol-1-yl)isonicotinic acid A.2-(5-Hydroxy-3,4-dimethyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

A mixture of 2-hydrazinylpyridine-4-carbonitrile (134 mg, 1 mmol,PREPARATION 2) and 2-methyl-3-oxo-butyric acid ethyl ester (158 mg, 1.1mmol) in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight.The reaction mixture was cooled, concentrated, and purified by flashcolumn chromatography (CH₂Cl₂) to afford the title compound (100 mg,47%) as an orange solid. [M+H] Calc'd for C₁₁H₁₀N₄O, 215. Found, 215.

B. 2-(5-hydroxy-3,4-dimethyl-1H-pyrazol-1-yl)isonicotinic acid

To a solution of2-(5-hydroxy-3,4-dimethyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (100mg, 0.47 mmol) in EtOH (5 mL) was added 5 M NaOH (2 mL) at rt, thenstirred at 90° C. for 1 h. The reaction mixture was cooled, acidifiedwith 1 N HCl to pH=3, filtered to give a yellow solid, thenrecrystallized from EtOH to afford the title compound (22 mg, 21%) as awhite solid. ¹H NMR (400 MHz, CD₃OD): δ 1.84 (3H, s), 2.23 (3H, s), 7.71(1H, dd, J=4.8, 1.2 Hz), 8.52 (1H, d, J=5.2 Hz), 8.65 (1H, s). [M+H]Calc'd for C₁₁H₁₁N₃O₃, 234. Found, 234.

Example 4 2-(5-Hydroxy-3-methyl-4-phenyl-1H-pyrazol-1-yl)isonicotinicacid A.2-(5-Hydroxy-3-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 29% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and3-oxo-2-phenyl-butyric acid ethyl ester according to the procedure forthe preparation of Example 3, part A. [M+H] Calc'd for C₁₆H₁₂N₄O, 277.Found, 277.

B. 2-(5-Hydroxy-3-methyl-4-phenyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 59% yield from2-(5-hydroxy-3-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 3, part B. ¹HNMR (400 MHz, CD₃OD): δ 2.31 (3H, s), 7.15 (1H, t, J=7.6 Hz), 7.30 (2H,t, J=7.6 Hz), 7.44 (2H, d, J=7.2 Hz), 7.64 (1H, d, J=4.8 Hz), 8.48 (1H,d, J=5.2 Hz), 8.81-8.82 (1H, m). [M+H] Calc'd for C₁₆H₁₃N₃O₃, 296.Found, 296.

Example 5 2-(3-(2-Fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)isonicotinicacid A.2-[3-(2-Fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 48% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-(2-fluorophenyl)-3-oxopropanoate according to the procedure for thepreparation of Example 3, part A. ¹H NMR (300 MHz, DMSO-d₆): δ 6.15-6.17(1H, m), 7.13-7.41 (4H, m), 8.07-8.12 (1H, m), 8.34 (1H, s), 8.48-8.50(1H, m), 11.64 (1H, s). [M+H] Calc'd for C₁₅H₉FN₄O, 281. Found, 281.

B. 2-(3-(2-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 75% yield from2-[3-(2-fluorophenyl)-5-hydroxy-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 3, part B. ¹HNMR (400 MHz, DMSO-d₆): δ 6.06 (1H, s), 7.29-7.34 (2H, m), 7.44-7.45(1H, m), 7.78-7.79 (1H, m), 8.01-8.05 (1H, m), 8.26 (1H, s), 8.68 (1H,d, J=5.2 Hz). [M+H] Calc'd for C₁₅H₁₀FN₃O₃, 300. Found, 300.

Example 6 2-(5-Hydroxy-3-propyl-1H-pyrazol-1-yl)isonicotinic acid A.2-(5-Hydroxy-3-propyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 44% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-oxohexanoate according to the procedure for the preparation of Example3, part A. [M+H] Calc'd for C₁₂H₁₂N₄O, 229. Found, 229.

B. 2-(5-Hydroxy-3-propyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 78% yield from2-(5-hydroxy-3-propyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 3, part B. ¹H NMR (400MHz, CD₃OD): δ 1.05 (3H, t, J=6.8 Hz), 1.71-1.80 (2H, m), 2.61 (3H, t,J=7.2 Hz), 4.87 (1H, s), 7.75 (1H, d, J=4.8 Hz), 8.58 (1H, d, J=5.2 Hz),8.83-8.85 (1H, m). [M+H] Calc'd for C₁₂H₁₃N₃O₃, 248. Found, 248.

Example 7 2-(3-(2-Chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl)isonicotinicacid A. Ethyl 3-(2-chlorophenyl)-3-oxopropanoate

Sodium hydride (1.45 g, 36 mmol) and diethyl carbonate (2.14 g, 18 mmol)were suspended in 10 ml of THF. 1-(2-Chlorophenyl)ethanone (1.4 g, 9mmol) was gradually added into the reaction flask, maintaining thereaction mixture temperature at 40° C. for 2 h. Then 1 mL of ethanol wasadded thereto and heated under reflux conditions for 4 h. After cooling,1 mL of ethanol was added and the mixture was poured onto ice water, andextracted with ether. Ether extracts are combined, washed with water,dried with anhydrous magnesium sulfate, and evaporated. The resultingoil is purified by flash column chromatography (PE/EA=50/1) to affordthe title compound (680 mg, 34%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ 1.24 (3H, t, J=6.8 Hz), 4.03 (2H, s), 4.19 (2H, q, J=6.8 Hz),7.31-7.36 (2H, m), 7.42-7.45 (2H, m). [M+H] Calc'd for C₁₁H₁₁ClO₃, 227.Found, 227.

B.2-[3-(2-Chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 75% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-(2-chlorophenyl)-3-oxopropanoate according to the procedure for thepreparation of Example 3, part A. [M+H] Calc'd for C₁₅H₉ClN₄O 297.Found, 297.

C. 2-(3-(2-Chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 72% yield from2-[3-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 3, part B. ¹HNMR (400 MHz, CD₃OD): δ 4.81 (1H, s), 7.35-7.37 (2H, m), 7.48-7.49 (1H,m), 7.78-7.79 (2H, m), 8.54-8.55 (2H, m). [M+H] Calc'd for C₁₅H₁₀ClN₃O₃,316. Found, 316.

Example 8 2-(3-Benzyl-5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid A.Ethyl 3-oxo-4-phenylbutanoate

To a solution of phenylacetyl chloride (1 mL, 7.56 mmol) was addeddropwise a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.09 g, 7.56mmol) and pyridine (1.3 mL) in CH₂Cl₂ (20 mL) at 0° C. The solution wasstirred for 30 min at 0° C., then allowed to warm slowly to rt andstirred overnight. The reaction mixture was then washed with 10% aqueousHCl (2×10 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated under reduced pressure. The crude residue was dissolved inEtOH (20 mL) and heated under reflux conditions for 4 h. The mixture wascooled to rt and then concentrated under reduced pressure. The resultingoil was purified by flash column chromatography (PE/EA=1/4) to affordthe title compound (600 mg, 38%) as a yellow oil. [M+H] Calc'd forC₁₂H₁₄O₃, 207. Found, 207.

B. 2-(3-Benzyl-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 53% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-oxo-4-phenylbutanoate according to the procedure for the preparationof Example 3, part A. [M+H] Calc'd for C₁₆H₁₂N₄O, 277. Found, 277.

C. 2-(3-Benzyl-5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 78% yield from2-(3-benzyl-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 3, part B. ¹H NMR (400MHz, CD₃OD): δ 3.96 (2H, s), 4.88 (1H, s), 7.24-7.27 (1H, m), 7.34-7.37(4H, m), 7.75-7.77 (1H, m), 8.58 (1H, d, J=5.2 Hz), 8.76 (1H, s). [M+H]Calc'd for C₁₆H₁₃N₃O₃, 296. Found, 296.

Example 9 2-(5-hydroxy-3-(methoxymethyl)-1H-pyrazol-1-yl)isonicotinicacid A.2-[5-Hydroxy-3-(methoxymethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 39% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl4-methoxy-3-oxobutanoate according to the procedure for the preparationof Example 3, part A. [M+H] Calc'd for C₁₁H₁₀N₄O₂, 231. Found, 231.

B: 2-(5-Hydroxy-3-(methoxymethyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 19% yield from2-[5-hydroxy-3-(methoxymethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 3, part B. ¹HNMR (400 MHz, CD₃OD): δ 3.33 (3H, s), 4.44 (2H, s), 4.78 (1H, s), 7.69(1H, d, J=5.2, 0.8 Hz), 8.46-7.48 (2H, m). [M+H] Calc'd for C₁₁H₁₁N₃O₄,250. Found, 250.

Example 10 2-(5-Hydroxy-3-(phenoxymethyl)-1H-pyrazol-1-yl)isonicotinicacid A.2-[5-Hydroxy-3-(phenoxymethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 58% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl3-oxo-4-phenoxybutanoate according to the procedure for the preparationof Example 3, part A. [M+H] Calc'd for C₁₆H₁₂N₄O₂, 293. Found, 293.

B. 2-(5-Hydroxy-3-(phenoxymethyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 49% yield from2-[5-hydroxy-3-(phenoxymethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 3, part B. ¹HNMR (400 MHz, CD₃OD): δ 4.75 (1H, s), 4.95 (2H, s), 6.85 (1H, t, J=7.6Hz), 6.92 (2H, d, J=8.0 Hz), 7.18 (2H, t, J=7.2 Hz), 7.68 (1H, dd,J=4.8, 1.2 Hz), 8.41-8.46 (2H, m). [M+H] Calc'd for C₁₆H₁₃N₃O₄, 312.Found, 312.

Example 11 2-(5-Hydroxy-1H-pyrazol-1-yl)isonicotinic acid A. Ethyl1-(4-cyanopyridin-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate

A mixture of 2-hydrazinylpyridine-4-carbonitrile (5.36 g, 40 mmol,PREPARATION 2), diethyl (ethoxymethylidene)propanedioate (8.64 g, 40mmol) and K₂CO₃ (10.76 g, 80 mmol) in H₂O (100 mL) was stirred at 100°C. for 4 h. The reaction mixture was cooled to rt and filtered to affordthe title compound (2.5 g, 24%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 1.19 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 7.38 (1H, dd,J=4.8, 1.6 Hz), 7.53 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.79 (1H, s).[M+H] Calc'd for C₁₂H₁₀N₄O₃, 259. Found, 259.

B. 2-(4-carboxy-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

To a solution of ethyl1-(4-cyanopyridin-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate (2.0 g, 7.7mmol) in EtOH (50 mL) was added 5 M NaOH (20 mL) at rt, then stirred at90° C. overnight. The reaction mixture was cooled, acidified with 1 NHCl to pH=3, filtered to give a yellow solid, then crystallized fromEtOH to afford the title compound (1.7 g, 88%) as a yellow solid. [M+H]Calc'd for C₁₀H₇N₃O₅, 250. Found, 250.

C. 2-(5-hydroxy-1H-pyrazol-1-yl)isonicotinic acid

A solution of2-(4-carboxy-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carboxylic acid (1.7g, 6.8 mmol) in conc. HCl (50 mL) was heated at 90° C. for 2 h. Thereaction mixture was cooled, extracted with EtOAc (200 mL), and washedwith water and brine. The organic phase was dried, concentrated, andrecrystallized from EtOH to afford the title compound (230 mg, 47%) as ayellow solid. ¹H NMR (400 MHz, CD₃OD): δ 4.86 (1H, s), 7.68 (1H, s),7.80 (1H, d, J=5.2 Hz), 8.60 (1H, d, J=1.6 Hz), 8.73 (1H, br). [M+H]Calc'd for C₉H₇N₃O₃, 206. Found, 206.

Preparation 3 2-Hydrazinylpyridine-4-carbonitrile hydrochloride salt

To a solution of 2-hydrazinylpyridine-4-carbonitrile (2.13 g, 16 mmol,PREPARATION 2) in EtOAc (10 mL) was added HCl (4 M in EtOAc, 15 mL) atrt. It was then stirred at rt for 30 min. The reaction mixture wasfiltered and washed with EtOAc and dried to give the title compound(3.13 g, 95%) as a yellow solid.

Example 12 2-(5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(dimethylamino)-1-(4-methylphenyl)prop-2-en-1-one

A solution of 1-(4-methylphenyl)ethanone (1.34 g, 10 mmol) in DMF-DMA(10 mL) was stirred at 100° C. overnight. The reaction mixture wascooled, concentrated, and purified by flash column chromatography(PE/EA=4:1-2:1) to give the title compound (1.40 g, 74%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 2.37 (3H, s), 2.95-3.11 (6H, m), 6.72(1H, d, J=12.0 Hz), 7.21 (2H, d, J=8.0 Hz), 7.78-7.82 (m, 3H).

B. 2-[5-(4-M ethylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

A mixture of 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (124mg, 0.6 mmol, PREPARATION 3) and(2E)-3-(dimethylamino)-1-(4-methylphenyl)prop-2-en-1-one (95 mg, 0.5mmol) in 2-methoxyethanol (3 mL) was stirred at 100° C. for 2 h. Thereaction mixture was cooled, concentrated, and dissolved in EtOAc andthen washed with water and brine. The organic phase was dried,concentrated, triturated with EA/PE (1:10, 5 mL), filtered, and dried togive the title compound (120 mg, 92%) as a yellow solid. ¹H NMR (400MHz, CDCl₃): δ 2.38 (3H, s), 6.49 (1H, d, J=1.6 Hz), 7.16 (4H, s), 7.38(1H, dd, J=5.2, 1.2 Hz), 7.76 (1H, d, J=1.2 Hz), 7.90 (1H, s), 8.44 (1H,d, J=5.2 Hz).

C. 2-(5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid

To a solution of2-[5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (120 mg,0.46 mmol) in EtOH (1 mL) was added 10 M NaOH (1 mL) at rt, then stirredat 90° C. for 1 h. The reaction mixture was cooled, acidified with 1 NHCl to pH=3, extracted with EtOAc (20 mL), and washed with water andbrine. The organic phase was dried, concentrated, triturated with EA/PE(1:1, 5 mL), filtered, and dried to give the title compound (60 mg, 47%)as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.30 (3H, s), 6.65 (1H,d, J=2.0 Hz), 7.13 (4H, s), 7.77 (1H, dd, J=4.8, 1.2 Hz), 7.82 (1H, d,J=1.2 Hz), 8.44 (1H, d, J=4.8 Hz), 13.97 (1H, br s). [M+H] Calc'd forC₁₆H₁₃N₃O₂, 280. Found, 280.

Example 13 2-(5-m-tolyl-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(Dimethylamino)-1-(3-methylphenyl)prop-2-en-1-one

The title compound was prepared in 35% yield from1-(3-methylphenyl)ethanone and DMF-DMA according to the procedure forthe preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ 2.39(3H, s), 2.79-3.11 (6H, m), 5.70 (1H, d, J=12.4 Hz), 7.24-7.31 (2H, m),7.66-7.71 (2H, m), 7.78 (1H, d, J=12.4 Hz).

B. 2-[5-(3-Methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in quantitative yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-(3-methylphenyl)prop-2-en-1-one accordingto the procedure for the preparation of Example 12, part B. ¹H NMR (400MHz, CDCl₃): δ 2.35 (3H, s), 6.51 (1H, d, J=1.6 Hz), 7.00 (1H, d, J=3.2Hz), 7.22 (3H, m), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.77 (1H, d, J=1.6 Hz),7.92 (1H, s), 8.42 (1H, d, J=4.8 Hz).

C. 2-(5-m-Tolyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 44% yield from2-[5-(3-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 12, part C. ¹H NMR (400MHz, DMSO-d₆): δ 2.27 (3H, s), 6.67 (1H, d, J=1.6 Hz), 6.97 (1H, d,J=7.6 Hz), 7.13-7.21 (3H, m), 7.78 (1H, d, J=4.4 Hz), 7.83 (1H, d, J=1.6Hz), 8.09 (1H, s), 8.43 (1H, d, J=5.2 Hz), 13.90 (1H, br s). [M+H]Calc'd for C₁₆H₁₃N₃O₂, 280. Found, 280.

Example 14 2-(5-(2,4-difluorophenyl)-1H-pyrazol-1-yl)isonicotinic acidA. (2E)-1-(2,4-Difluorophenyl)-3-(dimethylamino)prop-2-en-1-one

The title compound was prepared in 82% yield from1-(2,4-difluorophenyl)ethanone and DMF-DMA according to the procedurefor the preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ2.90 (3H, s), 3.11 (3H, s), 5.59-5.62 (1H, m), 6.77-6.83 (1H, m),6.88-6.93 (m, 1H), 7.75-7.83 (2H, m).

B. 2-[5-(2,4-Difluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 83% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-1-(2,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-oneaccording to the procedure for the preparation of Example 12, part B. ¹HNMR (400 MHz, CDCl₃): δ 6.51 (1H, d, J=1.6 Hz), 6.77-6.82 (1H, m),6.92-6.97 (1H, m), 7.34-7.40 (2H, m), 7.80 (1H, d, J=2.0 Hz), 8.20 (1H,s), 8.27 (1H, dd, J=5.2, 1.2 Hz).

C. 2-(5-(2,4-difluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 50% yield from2-[5-(2,4-difluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 12, part C. ¹HNMR (400 MHz, DMSO-d₆): δ 6.72 (1H, d, J=2.0 Hz), 7.13-7.18 (1H, m),7.23-7.28 (1H, m), 7.48-7.53 (1H, m), 7.72 (1H, dd, J=5.2, 1.2 Hz), 7.93(1H, d, J=1.6 Hz), 8.22 (1H, s), 8.33 (1H, d, J=5.2 Hz), 13.92 (1H, brs). [M+H] Calc'd for C₁₅H₉F₂N₃O₂, 302. Found, 302.

Example 15 2-(5-(3,4-difluorophenyl)-1H-pyrazol-1-yl)isonicotinic acidA. (2E)-1-(3,4-Difluorophenyl)-3-(dimethylamino)prop-2-en-1-one

The title compound was prepared in 84% yield from1-(3,4-difluorophenyl)ethanone and DMF-DMA according to the procedurefor the preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ2.93 (3H, s), 3.16 (3H, s), 5.62 (1H, d, J=12.0 Hz), 7.13-7.20 (1H, m),7.63-7.76 (2H, m), 7.83 (1H, d, J=12.0 Hz).

B. 2-[5-(3,4-difluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 83% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-1-(3,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-oneaccording to the procedure for the preparation of Example 12, part B. ¹HNMR (400 MHz, CDCl₃): δ 6.50 (1H, d, J=1.6 Hz), 7.01-7.04 (1H, m),7.11-7.18 (2H, m), 7.38-7.40 (1H, m), 7.77 (1H, d, J=2.0 Hz), 8.12 (1H,s), 8.36 (1H, d, J=4.8 Hz).

C. 2-(5-(3,4-difluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 48% yield from2-[5-(3,4-difluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 12, part C. ¹HNMR (400 MHz, DMSO-d6): δ 6.74 (1H, d, J=1.2 Hz), 7.11-7.13 (1H, m),7.37-7.46 (2H, m), 7.76-7.78 (1H, m), 7.87 (1H, d, J=1.6 Hz), 8.17 (1H,s), 8.41 (1H, d, J=5.2 Hz), 13.97 (1H, br s). [M+H] Calc'd forC₁₅H₉F₂N₃O₂, 302. Found, 302.

Example 16 2-(5-(3-fluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(dimethylamino)-1-(3-fluorophenyl)prop-2-en-1-one

The title compound was prepared in 92% yield from1-(3-fluorophenyl)ethanone and DMF-DMA according to the procedure forthe preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ 2.93(3H, s), 3.15 (3H, s), 5.65 (1H, d, J=12.4 Hz), 7.11-7.16 (1H, m),7.34-7.39 (1H, m), 7.57-7.67 (2H, m), 7.81 (1H, d, J=12.4 Hz).

B. 2-[5-(3-fluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 98% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-(3-fluorophenyl)prop-2-en-1-one accordingto the procedure for the preparation of Example 12, part B. ¹H NMR (400MHz, CDCl₃): δ 6.53 (1H, d, J=1.6 Hz), 6.99-7.10 (3H, m), 7.29-7.35 (1H,m), 7.38-7.40 (1H, m), 7.78 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.38 (1H,d, J=4.8 Hz).

C. 2-(5-(3-fluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 57% yield from2-[5-(3-fluorophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 12, part C. ¹H NMR (400MHz, DMSO-d₆): δ 6.76 (1H, d, J=1.2 Hz), 6.77-7.19 (3H, m), 7.36-7.39(1H, m), 7.78 (1H, dd, J=5.2, 1.2 Hz), 7.87 (1H, d, J=1.2 Hz), 8.15 (1H,s), 8.42 (1H, d, J=4.8 Hz), 13.86 (1H, br s). [M+H] Calc'd forC₁₅H₁₀FN₃O₂, 284. Found, 284.

Example 17 2-(5-(3-hydroxyphenyl)-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one

The title compound was prepared in 89% yield from1-(3-methoxyphenyl)ethanone and DMF-DMA according to the procedure forthe preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ 2.94(3H, s), 3.13 (3H, s), 3.85 (3H, s), 7.69 (1H, d, J=12.4 Hz), 6.98-7.01(1H, m), 7.29-7.46 (3H, m), 7.79 (1H, d, J=12.4 Hz).

B. 2-(5-(3-methoxyphenyl)-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 98% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one accordingto the procedure for the preparation of Example 12, part B. ¹H NMR (400MHz, CDCl₃): δ 3.78 (3H, s), 6.53 (1H, s), 6.81-6.85 (2H, m), 6.90-6.93(1H, m), 7.24-7.28 (1H, m), 7.38 (1H, dd, J=5.6, 1.2 Hz), 7.77 (1H, d,J=2.0 Hz), 7.93 (1H, s), 8.44 (1H, dd, J=5.2, 0.8 Hz).

C. 2-[5-(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared in 93% yield from2-[5-(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 12, part C. ¹H NMR (300MHz, DMSO-d₆): δ 3.67 (3H, s), 6.71-6.92 (4H, m), 7.21-7.26 (1H, m),7.78-7.84 (2H, m), 8.09 (1H, s), 8.45 (1H, d, J=5.1 Hz).

D. 2-(5-(3-hydroxyphenyl)-1H-pyrazol-1-yl)isonicotinic acid

To a solution of2-[5-(3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid (160mg, 0.54 mmol) in CH₂Cl₂ (5 mL) was added 1 M BBr₃ in CH₂Cl₂ (5 mL) at0° C., then stirred at 45° C. overnight. The reaction mixture wascooled, concentrated and dissolved with EtOAc, then washed with waterand brine. The organic phase was dried, concentrated and purified byprep-HPLC to give the title compound (54 mg, 35%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 6.60-6.65 (3H, m), 6.71 (1H, dd, J=8.4, 2.0Hz), 7.11 (1H, t, J=8.0 Hz), 7.78-7.82 (2H, m), 8.04 (1H, s), 8.48 (1H,d, J=5.2 Hz), 9.46 (1H, s), 13.93 (1H, br s). [M+H] Calc'd forC₁₅H₁₁N₃O₃, 282. Found, 282.

Example 18 2-(5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one

The title compound was prepared in 88% yield from1-(4-methoxyphenyl)ethanone and DMF-DMA according to the procedure forthe preparation of Example 12, part A. ¹H NMR (400 MHz, CDCl₃): δ2.88-3.06 (6H, br s), 3.85 (3H, s), 5.71 (1H, d, J=12.0 Hz), 6.91 (2H,d, J=8.8 Hz), 7.84 (1H, d, J=12.0 Hz), 7.91 (2H, d, J=8.8 Hz).

B. 2-[5-(4-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 100% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one accordingto the procedure for the preparation of Example 12, part B. ¹H NMR (400MHz, CDCl₃): δ 3.84 (3H, s), 6.46 (1H, d, J=5.6 Hz), 6.88 (2H, dd,J=6.8, 2.0 Hz), 7.20 (2H, dd, J=6.4, 2.0 Hz), 7.37 (1H, dd, J=5.2, 1.6Hz), 7.75 (1H, d, J=1.6 Hz), 7.91 (1H, s), 8.44 (1H, dd, J=4.8, 0.8 Hz).

C. 2-[5-(4-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared in 79% yield from2-[5-(4-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 12, part C. ¹H NMR (300MHz, DMSO-d₆): δ 3.76 (3H, s), 6.61 (1H, s), 6.88-6.91 (2H, m),7.16-7.19 (2H, m), 7.76-7.80 (2H, m), 8.06 (1H, s), 8.45 (1H, d, J=5.1Hz).

D. 2-(5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 32% yield from2-[5-(4-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 17, part D. ¹H NMR (400MHz, DMSO-d₆): δ 6.56 (1H, d, J=2.0 Hz), 6.71 (2H, d, J=8.4 Hz), 7.05(2H, d, J=8.4 Hz), 7.76-7.78 (2H, m), 8.02 (1H, s), 8.48 (1H, d, J=4.8Hz), 9.63 (1H, s), 13.89 (1H, br s). [M+H] Calc'd for C₁₅H₁₁N₃O₃, 282.Found, 282.

Example 19 2-(5-(4-(methylsulfonyl)phenyl)-1H-pyrazol-1-yl)isonicotinicacid A.(2E)-3-(dimethylamino)-1-[4-(methylsulfonyl)phenyl]prop-2-en-1-one

The title compound was prepared in 87% yield from1-[4-(methylsulfonyl)phenyl]ethanone and DMF-DMA according to theprocedure for the preparation of Example 12, part A. ¹H NMR (400 MHz,CDCl₃): δ 2.96 (3H, s), 3.06 (3H, s), 3.19 (3H, s), 5.66 (1H, d, J=12Hz), 7.83 (1H, d, J=12 Hz), 7.96-8.04 (4H, m).

B.2-{5-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 100% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-[4-(methylsulfonyl)phenyl]prop-2-en-1-oneaccording to the procedure for the preparation of Example 12, part B. ¹HNMR (400 MHz, CDCl₃): δ 3.10 (3H, s), 6.58 (1H, d, J=1.6 Hz), 7.39 (1H,dd, J=5.2, 1.2 Hz), 7.51 (2H, d, J=8.4 Hz), 7.81 (1H, d, J=1.6 Hz), 7.93(2H, d, J=8.4 Hz), 8.20 (1H, s), 8.29 (1H, d, J=5.2 Hz).

C. 2-(5-(4-(methylsulfonyl)phenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 44% yield from2-{5-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 12, part C. ¹HNMR (400 MHz, DMSO-d₆): δ 3.25 (3H, s), 6.84 (1H, d, J=1.6 Hz), 7.57(2H, d, J=8.4 Hz), 7.05 (1H, dd, J=4.8, 1.2 Hz), 7.87-7.93 (3H, m), 8.22(1H, s), 8.40 (1H, d, J=4.8 Hz), 13.98 (1H, br s). [M+H] Calc'd forC₁₆H₁₃N₃O₄S, 344. Found, 344.

Example 20 2-(5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1-yl)isonicotinicacid A.(2E)-3-(dimethylamino)-1-(3-methoxy-4-methylphenyl)prop-2-en-1-one

The title compound was prepared in 49% yield from1-(3-hydroxy-4-methylphenyl)ethanone and DMF-DMA according to theprocedure for the preparation of Example 12, part A. ¹H NMR (400 MHz,CDCl₃): δ 2.25 (3H, s), 2.95-3.10 (6H, m), 3.89 (3H, s), 5.72 (1H, d,J=12.0 Hz), 7.14 (1H, d, J=7.6 Hz), 7.37 (1H, dd, J=7.6, 1.2 Hz), 7.45(1H, d, J=1.2 Hz) 7.80 (1H, d, J=12.4 Hz). [M+H] Calc'd for C₁₂H₁₅NO₂,220. Found, 220.

B.2-[5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 100% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-(3-methoxy-4-methylphenyl)prop-2-en-1-oneaccording to the procedure for the preparation of Example 12, part B. ¹HNMR (400 MHz, CDCl₃): δ 2.24 (3H, s), 3.73 (3H, s), 6.51 (1H, d, J=1.6Hz), 6.71-6.75 (2H, m), 7.08 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=5.2, 1.2Hz), 7.77 (1H, d, J=1.2 Hz), 7.90 (1H, s), 8.47 (1H, d, J=5.2 Hz). [M+H]Calc'd for C₁₇H₁₄N₄O, 291. Found, 291.

C. 2-(5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 53% yield from2-[5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 12, part C. ¹HNMR (400 MHz, DMSO-d₆): δ 2.13 (3H, s), 3.63 (3H, s), 6.69-6.71 (2H, m),6.79 (1H, d, J=1.6 Hz), 7.07 (1H, d, J=7.6 Hz), 7.78-7.83 (2H, m), 8.08(1H, s), 8.48 (1H, d, J=4.8 Hz), 13.92 (1H, br s). [M+H] Calc'd forC₁₇H₁₅N₃O₃, 310. Found, 310.

Example 21 2-(5-(3-hydroxy-4-methylphenyl)-1H-pyrazol-1-yl)isonicotinicacid

The title compound was prepared in 24% yield from2-(5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1-yl)isonicotinic acidaccording to the procedure for the preparation of Example 17, part D. ¹HNMR (400 MHz, DMSO-d₆): δ 2.09 (3H, s), 6.57-6.61 (3H, m), 7.00 (1H, d,J=7.2 Hz), 7.79 (2H, dd, J=4.0, 2.0 Hz), 8.02 (1H, s), 8.50 (1H, d,J=4.8 Hz), 9.30 (1H, s), 13.92 (1H, br s). [M+H] Calc'd for C₁₆H₁₃N₃O₃,296. Found, 296.

Example 22 2-(5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1-yl)isonicotinicacid A.(2E)-1-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one

The title compound was prepared in 43% yield from1-(4-chloro-3-hydroxyphenyl)ethanone and DMF-DMA according to theprocedure for the preparation of Example 12, part A. ¹H NMR (400 MHz,CDCl₃): δ 2.94 (3H, br s), δ 3.16 (3H, br s), 3.97 (3H, s), 5.67 (1H, d,J=12.4 Hz), 7.38 (2H, s), 7.56 (1H, s), 7.81 (1H, d, J=12.4 Hz). [M+H]Calc'd for C₁₁H₁₂ClNO₂, 240. Found, 240.

B.2-[5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 74% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-1-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-oneaccording to the procedure for the preparation of Example 12, part B. ¹HNMR (400 MHz, CDCl₃): δ 3.82 (3H, s), 6.53 (1H, d, J=2.0 Hz), 6.78 (1H,d, J=2.4 Hz), 6.89 (1H, d, J=1.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.39 (1H,dd, J=5.2, 1.2 Hz), 7.78 (1H, d, J=1.2 Hz), 8.07 (1H, s), 8.39 (1H, dd,J=5.2, 0.8 Hz). [M+H] Calc'd for C₁₆H₁₁ClN₄O, 311. Found, 311.

C. 2-(5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 71% yield from2-[5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 12, part C. ¹HNMR (400 MHz, CDCl₃): δ 3.79 (3H, s), 6.55 (1H, d, J=1.2 Hz), 6.79 (1H,s), 6.87 (1H, d, J=2.0 Hz), 7.30 (1H, d, J=8.4 Hz), 7.82 (2H, s), 8.15(1H, s), 8.32 (1H, s), 8.46 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 23 2-(5-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-1-yl)isonicotinicacid

The title compound was prepared in 19% yield from2-(5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1-yl)isonicotinic acidaccording to the procedure for the preparation of Example 17, part D. ¹HNMR (400 MHz, CD₃OD): δ 6.51 (1H, s), 6.60 (1H, dd, J=8.4, 2.0 Hz), 6.66(1H, d, J=2.0 Hz), 7.14 (1H, d, J=8.4 Hz), 7.68 (1H, s), 7.77 (1H, d,J=4.4 Hz), 7.93 (1H, s), 8.39 (1H, s). [M+H] Calc'd for C₁₅H₁₀ClN₃O₃,316. Found, 316.

Example 24 2-[5-(1H-indazol-6-yl)-1H-pyrazol-1-yl]pyridine-4-carboxylicacid A. 1-(1H-indazol-6-yl)ethanone (24-a)

To a solution of 6-bromo-1H-indazole (5.0 g, 25.4 mmol) in 40 mL THF wasadded dropwise n-BuLi (2.5M, 30 mL, 76.2 mmol) at −65° C., and themixture was stirred for 2 h. Then, N-methoxy-N-methylacetamide (2.9 g,27.9 mmol) was added. The reaction mixture was stirred for another 2 hat −65° C., then quenched with 40 mL H₂O. The mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with 100 mLbrine, dried, and concentrated to dryness. The residue was purified byflash column chromatography (PE/EA=40/1) to give the title compound 24-a(370 mg, 9%) as a yellow solid. [M+H] Calc'd for C₉H₈N₂O, 161. Found,161.

B. 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)ethanone(24-b1) and1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-6-yl)ethanone (24-b2)

To a solution of 1-(1H-indazol-6-yl)ethanone 24-a (200 mg, 1.25 mmol) in4 mL DMF was added NaH (77 mg, 1.9 mmol) at 0-5° C., and the mixture wasstirred for 1 h at 0-5° C. 2-(Trimethylsilyl)ethoxymethyl chloride (215mg, 1.29 mmol) was then added. The mixture was stirred for 2 h prior tothe addition of 5 mL H₂O. The reaction mixture was extracted (3×10 mLEtOAc), dried, and concentrated to dryness to give a mixture of theproducts 24-b1 and 24-b2 (280 mg, 77%) as a yellow oil, which was usedwithout further purification for the next synthetic step. [M+H] Calc'dfor C₁₅H₂₂N₂O₂Si, 291. Found, 291.

C.3-(dimethylamino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)prop-2-en-1-one(24-c1) and3-(dimethylamino)-1-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-6-yl)prop-2-en-1-one(24-c2)

To a regioisomeric mixture of compound 3 (700 mg, 2.4 mmol) in 10 mL DMFwas added 2 mL DMF-DMA, and the mixture was heated to 115° C. andstirred for 4 h. The reaction mixture was cooled and concentrated todryness to give the crude product 24-c1 and 24-c2 (900 mg, 100%) as ayellow oil, and was used without further purification for the nextsynthetic step. [M+H] Calc'd for C₁₈H₂₇N₃O₂Si, 346. Found, 346.

D. 2-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinonitrile(24-d1) and2-(5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinonitrile(24-d2)

A mixture of compounds 24-c1 and 24-c2 (900 mg, 2.6 mmol) and2-hydrazinylpyridine-4-carbonitrile (350 mg, 2.6 mmol) in EtOH (10 mL)and AcOH (2 mL) was stirred at 90° C. overnight. The reaction mixturewas cooled, concentrated, and purified by prep-HPLC to afford compounds24-d1 and 24-d2 (390 mg, 36%), and was used without further purificationfor the next synthetic step. [M+H] Calc'd for C₂₂H₂₄N₆OSi, 417. Found,417.

E.2-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinicacid (24-e1) and2-(5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinicacid (24-e2)

To a solution of compounds 24-d1 and 24-d2 (390 mg, 0.94 mmol) in EtOH(10 mL) was added 5 M NaOH (2 mL) at rt, then stirred at 90° C. for 1 h.The reaction mixture was cooled, acidified with 1 N HCl to pH=3,filtered to give a yellow solid, and recrystallized from EtOH to affordcompounds 24-e1 and 24-e2 (230 mg, 56%) as a white solid, which was usedwithout further purification for the next synthetic step. [M+H] Calc'dfor C₂₂H₂₅N₅O₃Si, 436. Found, 436.

F. 2-[5-(1H-indazol-6-yl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

The solution of compounds 24-e1 and 24-e2 (50 mg, 0.12 mmol) inHCl/EtOAc (6 M, 10 mmol) was stirred overnight at rt. The reactionmixture was filtered, and the solids were stirred with EtOAc/PE (0.5mL/5 mL) for 1 h. After filtration, the solids were washed with hexaneto give the title compound (13 mg, 37%) as a yellow solid. ¹H NMR (400MHz, MeOD-d₄): δ 6.75 (1H, s), 7.06 (1H, dd, J=6.8, 1.6 Hz), 7.51 (1H,s), 7.77 (1H, d, J=8.4 Hz), 7.88 (2H, s), 8.14 (2H, d, J=1.2 Hz), 8.45(1H, d, J=2.0 Hz). [M+H] Calc'd for C₁₆H₁₁N₅O₂, 306. Found, 306.

Example 25 Methyl2-[5-(1H-indazol-6-yl)-1H-pyrazol-1-yl]pyridine-4-carboxylate A. Methyl2-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinate(25-a1) and methyl2-(5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-6-yl)-1H-pyrazol-1-yl)isonicotinate(25-a2)

To a solution of compound 24-e1 and 24-e2 (50 mg, 0.12 mmol) inCH₂Cl₂/DMF (2 mL/1 drop) was added oxalyl chloride (0.5 mL), and themixture was stirred for 1 h at rt. Then the reaction mixture was addeddropwise to MeOH (1 mL), and the resultant mixture was stirred for 30min at rt. Removal of volatiles provided compounds 25-a1 and 25-a2 (60mg, 100%) as a yellow solid, which was used without further purificationfor the next synthetic step. [M+H] Calc'd for C₂₃H₂₇N₅O₃Si, 450. Found,450.

B. Methyl 2-[5-(1H-indazol-6-yl)-1H-pyrazol-1-yl]pyridine-4-carboxylate

The solution of compounds 25-a1 and 25-a2 (60 mg, 0.12 mmol) inTFA/CH₂Cl₂ (0.5 mL/2 mL) was stirred overnight at rt. The mixture wasconcentrated, and the residue was adjusted to pH=8 with saturated aq.NaHCO₃. The mixture was extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered,concentrated, and purified by prep-HPLC to afford the title compound (10mg, 28%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄): δ 3.96 (3H, s),6.74 (1H, d, J=1.6 Hz), 7.00 (1H, dd, J=8.4, 1.2 Hz), 7.50 (1H, s), 7.74(1H, d, J=8.4 Hz), 7.87 (2H, m), 8.07 (1H, s), 8.13 (1H, s), 8.46 (1H,d, J=7.2 Hz). [M+H] Calc'd for C₁₇H₁₃N₅O₂, 320. Found, 320.

Example 26 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinic acid A.(E)-3-(dimethylamino)-1-phenylprop-2-en-1-one

A mixture of acetophenone (8.0 g, 66.58 mmol, 1.0 eq) and DMF (5.8 g,79.90 mmol, 1.2 eq.) in 10.0 mL of DMA in a 25-mL microwave vial wasirradiated at 115° C. for 0.5-1 h. The crude reaction mixture wastriturated with n-hexane, and the resultant solid was filtered to affordthe title compound as a pale yellow solid (3.4 g. 29.3% yield). [M+H]Calc'd for C₁₁H_(n)NO, 176. Found, 176.

B. 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinonitrile

To a solution of 2-hydrazinylisonicotinonitrile (100 mg, 0.75 mmol, 1.0eq., PREPARATION 2) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one(132 mg, 0.75 mmol, 1.0 eq.) in ethanol (10 mL) was added 2-5 drops ofAcOH. The reaction mixture was under reflux conditions for 12 h. Afterreaction completion, volatiles were removed under reduced pressure, andthe resultant crude material was purified by flash column chromatography(20% EtOAc/hexane) to obtain the title compound as a yellow oil (150 mg,81% yield). [M+H] Calc'd for C₁₅H₁₀N₄, 247.09. Found 247.

C. 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinic acid

To a stirred solution of 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinonitrile(100 mg, 0.41 mmol) in EtOH (10 mL) was added a solution of 25% NaOH inwater (1.0 mL). The reaction mixture was heated under reflux conditionsat 80° C. for 1 h. After reaction completion, the solvent was removed,and the resultant mixture was diluted with water, and the pH wasadjusted to pH=4-5 with 2.0 N HCl. The mixture was extracted with EtOAc(3×15 mL), the combined organic layers were dried over Na₂SO₄, and thesolvent was removed to obtain pale yellow solid, which was washed withhexane and dried under reduced pressure to afford the title compound (60mg, 55% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.5 (S, 1H), 8.2 (d, 1H,J=2.1 Hz), 7.9 (s, 1H), 7.78 (s, 1H), 7.7 (d, 1H, J=2.7 Hz), 7.3 (m,2H), 7.2 (m, 1H), 6.65 (s, 2H). [M+H] Calc'd for C₁₅H₁₁N₃O₂, 266. Found,266.

Example 27 2-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid A.(E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one

The title compound was prepared in 39% yield from1-(4-fluorophenyl)ethanone according to the procedure for thepreparation of Example 26, part A. ¹H NMR (500 MHz, CDCl₃) δ 7.91 (dd,2H, J=5.8, 7.7 Hz), 7.79 (d, 1H, J=12.6 Hz), 7.0 (t, 2H, J=8.7, 7.7 Hz),5.6 (d, 1H, J=12.6 Hz), 3.14 (s, 3H), 2.92 (s, 3H). [M+H] Calc'd forC₁₁H₁₂FNO, 193. Found, 193.

B. 2-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)isonicotinonitrile

The title compound was prepared in 32% yield from2-hydrazinylisonicotinonitrile (PREPARATION 2) and(E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one according to theprocedure for the preparation of Example 26, part B. ¹H NMR (500 MHz,CDCl₃) δ 8.36 (d, 1H, J=4.8 Hz), 8.0 (s, 1H), 7.7 (s, 1H), 7.37 (d, 1H,J=3.8 Hz), 7.25 (d, 2H, J=5.8), 7.0 (t, 2H, J=8.7 Hz, 1H), 6.45 (s, 1H).[M+H] Calc'd for C₁₅H₉FN₄, 265. Found, 265.

C. 2-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 35% yield from2-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)isonicotinonitrile according tothe procedure for the preparation of Example 26, part C. ¹H NMR (500MHz, DMSO-d₆): δ 8.8 (d, 1H, J=4.4 Hz), 8.5 (s, 1H), 8.26 (s, 1H), 8.2(d, 1H, J=4.4 Hz), 7.74 (t, 2H, J=7.7 Hz), 7.54 (t, 2H, J=7.7 Hz), 7.1(s, 1H). [M+H] Calc'd for C₁₅H₁₀FN₃O₂, 283. Found, 283.

Example 282-(5-(3-hydroxy-4-(methylsulfonyl)phenyl)-1H-pyrazol-1-yl)isonicotinicacid A. 5-acetyl-2-(methylsulfanyl)phenyl acetate

To a solution of 2-(methylsulfanyl)phenol (4.2 g, 30 mmol) in CS₂ (50mL) was added dropwise acetyl chloride (5.2 g, 66 mmol) at 0° C. for 10min. The resulting mixture was stirred for 20 min at rt. Then AlCl₃(10.8 g, 81 mmol) was added, and the reaction mixture was heated underreflux conditions for 3 h. The reaction mixture was poured into icewater, conc. HCl (5 mL) was added, and the reaction mixture wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The residue was dissolved inCH₂Cl₂ (50 mL), cooled to 0° C. and treated successively with acetylchloride (1.2 g, 15 mmol) and triethylamine (1.5 g, 15 mmol). Themixture was stirred at rt for 2 h and poured into water. Afterseparation of the layers, the organic phase was washed successively withwater, 3 N HCl and 10% aq. KHCO₃, dried over Na₂SO₄, and evaporated todryness. Recrystallization of the resulting solid from benzene-hexaneafforded the title compound (2.5 g, 37%). ¹H NMR (400 MHz, CDCl₃): δ2.08 (3H, s), 2.47 (3H, s), 2.55 (3H, s), 7.26 (1H, d, J=4.8 Hz), 7.57(1H, d, J=4.8 Hz), 7.60 (1H, s).

B. 5-acetyl-2-(methylsulfonyl)phenyl acetate

To a solution of 5-acetyl-2-(methylsulfanyl)phenyl acetate (2.24 g, 10mmol) in CH₂Cl₂ (20 mL) was added mCPBA (8.62 g, 50 mmol) at 0° C. andthe mixture was stirred at rt for 3 h. A solution of NaHCO₃ was addedand extracted with CH₂Cl₂. The organic phase was washed successivelywith water, 3 N HCl and 10% aq. KHCO₃, dried over Na₂SO₄, and evaporatedto afford the crude product (2.1 g, 82%). ¹H NMR (400 MHz, CDCl₃): δ2.10 (3H, s), 2.57 (3H, s), 2.84 (3H, s), 7.86 (1H, d, J=4.8 Hz), 7.93(1H, s), 8.05 (1H, d, J=4.8 Hz).

C. 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenylacetate

A solution of 5-acetyl-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.8mmol) and DMF-DMA (1.2 g, 10 mmol) in DMF (20 mL) was stirred at 100° C.overnight. The reaction mixture was cooled, concentrated, and purifiedby flash column chromatography (PE/EtOAc=4:1-2:1) to give the titlecompound (0.5 g, 30%). [M+H] Calc'd for C₁₃H₁₇NO₄S, 284. Found, 284.

D.2-{5-[3-methoxy-4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

A mixture of5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenyl acetate(1.5 g, 5.3 mmol) and 2-hydrazinylisonicotinonitrile (0.8 g, 6 mmol,PREPARATION 2) in EtOH (15 mL) and AcOH (3 mL) was stirred at 90° C.overnight. The reaction mixture was cooled, concentrated, and purifiedby prep-HPLC to afford the title compound (270 mg, 14%). ¹H NMR (400MHz, CDCl₃): δ 3.26 (3H, s), 3.96 (3H, s), 6.58 (1H, d, J=1.6 Hz), 6.96(1H, dd, J=8.4, 1.2 Hz), 7.05 (1H, d, J=1.2 Hz), 7.41 (1H, dd, J=4.8,1.2 Hz), 7.81 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.18 (1H, s),8.35 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₄N₄O₃S, 355. Found, 355.

E.2-{5-[3-methoxy-4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

To a solution of2-{5-[3-methoxy-4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrile(270 mg, 0.76 mmol) in EtOH (5 mL) was added 5 M NaOH (2 mL) at rt, thenstirred at 90° C. for 1 h. The reaction mixture was cooled, acidifiedwith 1 N HCl to pH=3, filtered to give a yellow solid, thenrecrystallized from EtOH to afford the title compound (230 mg, 80%) as awhite solid. [M+H] Calc'd for C₁₇H₁₅N₃O₅S, 374. Found, 374.

F.2-(5-(3-hydroxy-4-(methylsulfonyl)phenyl)-1H-pyrazol-1-yl)isonicotinicacid

The title compound was prepared in 6% yield from2-{5-[3-methoxy-4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 17, partD. ¹H NMR (400 MHz, DMSO-d₆): δ 3.21 (3H, s), 6.78 (1H, d, J=1.6 Hz),6.89-6.92 (2H, m), 7.65 (1H, d, J=8.0 Hz), 7.81-7.82 (1H, m), 7.90 (1H,d, J=2.0 Hz), 8.16 (1H, s), 8.48 (1H, d, J=4.8 Hz), 11.12 (1H, br).[M+H] Calc'd for C₁₆H₁₃N₃O₅S, 360. Found, 360.

Example 29 2-(3-methyl-5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid A.(2E)-3-(dimethylamino)-1-(4-methylphenyl)but-2-en-1-one

A solution of 1-(4-methylphenyl)ethanone (2.0 g, 15 mmol) in(1,1-dimethoxy-ethyl)-dimethyl-amine was heated to 120° C. and stirredovernight. The reaction mixture was cooled and concentrated to dryness.The residue was stirred with 25 mL hexane for 1 h and filtered. Thesolids were washed with hexane and then dried to give the title compound(1.8 g, 60%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 2.37 (3H, s),2.65 (3H, s), 3.07 (6H, s), 5.68 (1H, s), 7.19 (2H, d, J=7.6 Hz), 7.77(2H, d, J=8.0 Hz). [M+H] Calc'd for C₁₃H₁₇NO, 204. Found, 204.

B.2-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of (2E)-3-(dimethylamino)-1-(4-methylphenyl)but-2-en-1-one(227 mg, 1.1 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol,PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixturewas heated under reflux conditions overnight before being cooled andconcentrated to dryness. The residue was adjusted to pH>8 with saturatedaq. K₂CO₃ and then extracted with EtOAc (3×10 mL). The combined organiclayers were washed with 20 mL brine, dried, and concentrated to drynessto give the title compound (170 mg, 55.6%) as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ 2.38 (6H, s), 6.30 (1H, s), 7.15 (4H, s), 7.33 (1H,d, J=4.0 Hz), 7.78 (1H, s), 8.44 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₁₇H₁₄N₄, 275. Found, 275.

C. 2-(3-methyl-5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 22% yield from2-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (300 MHz, DMSO-d₆): δ 2.28 (3H, s), 2.30 (3H, s), 6.44 (1H, s), 7.15(4H, s), 7.72 (1H, d, J=4.5 Hz), 8.06 (1H, s), 8.70 (1H, d, J=4.5 Hz).[M+H] Calc'd for C₁₇H₁₅N₃O₂, 294. Found, 294.

Example 30 2-(3-ethyl-5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid A.1-(4-methylphenyl)pentane-1,3-dione

To a suspension of NaH (60%, 106 mg, 4.44 mmol) in 2 mL propionic acidethyl ester was added 1-(4-methylphenyl)ethanone (500 mg, 3.7 mmol) at0-5° C. The reaction mixture was stirred overnight at rt. Water wasadded, and the mixture was extracted with EtOAc (3×50 mL). The organiclayers were washed with brine, dried over Na₂SO₄, and concentrated todryness. The residue was purified by flash column chromatography(PE/EtOAc=10/1) to give the title compound (370 mg, 52%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃): δ 1.22 (3H, m), 2.45 (5H, m), 6.17 (2H,s), 7.27 (2H, d, J=10 Hz), 7.81 (2H, d, J=11.2 Hz). [M+H] Calc'd forC₁₂H₁₄O₂, 191. Found, 191.

B. 2-[3-ethyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of 1-(4-methylphenyl)pentane-1,3-dione (370 mg, 1.9 mmol)and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated underreflux conditions overnight before being cooled and concentrated todryness. The residue was adjusted to pH>8 with saturated aq. K₂CO₃, thenextracted by EtOAc (10 mL×3). The combined organic layers were washedwith 20 mL brine, dried over Na₂SO₄, concentrated, and purified by flashcolumn chromatography (PE/EtOAc=10/1) to give the title compound (560mg, 77%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 1.33 (3H, m),2.38 (3H, s), 2.76 (2H, m), 6.33 (1H, s), 7.15 (4H, m), 7.31 (1H, m),7.82 (1H, s), 8.42 (1H, m). [M+H] Calc'd for C₁₅H₁₆N₄, 289. Found, 289.

C. 2-(3-ethyl-5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 69% yield from2-[3-ethyl-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.26 (3H, m), 2.30 (3H, s), 2.66 (2H, m), 6.33(1H, s), 7.12 (4H, m), 7.72 (1H, m), 8.07 (1H, s), 8.39 (1H, d, J=4.8Hz), 13.88 (1H, s). [M+H] Calc'd for C₁₅H₁₇N₃O₂, 308. Found, 308.

Example 31 2-(5-methyl-1H-pyrazol-1-yl)isonicotinic acid A.2-(5-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (31-a1) and2-(3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (31-a2)

A mixture of 2-hydrazinylisonicotinonitrile (268 mg, 2 mmol, PREPARATION2) and (3E)-4-(dimethylamino)but-3-en-2-one (339 mg, 3 mmol) in EtOH (5mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reactionmixture was cooled, concentrated, and purified by prep-HPLC to affordcompound 31-a1 (90 mg) and compound 31-a2 (150 mg). 31-a1: ¹H NMR (400MHz, CDCl3): δ 2.38 (3H, s), 6.29 (1H, d, J=2.8 Hz), 7.32 (1H, dd J=5.2,1.2 Hz), 8.18 (1H, s), 8.42 (1H, d, J=2.8 Hz), 8.52-8.53 (1H, m). [M+H]Calc'd for C₁₀H₈N₄, 185. Found, 185.

31-a2: ¹H NMR (400 MHz, CDCl₃): δ 2.71 (3H, s), 6.22 (1H, d, J=0.8 Hz),7.36 (1H, dd, J=4.8, 1.2 Hz), 7.61 (1H, d, J=1.2 Hz), 8.26 (1H, d, J=2.8Hz), 8.57 (1H, dd, J=5.2, 0.8 Hz). [M+H] Calc'd for C₁₀H₈N₄, 185. Found,185.

B. 2-(5-methyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 53% yield from2-(5-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (31-a1) according tothe procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 2.31 (3H, s), 6.42 (1H, d, J=2.8 Hz), 7.70 (1H, ddJ=5.2, 1.2 Hz), 8.25 (1H, s), 8.53 (1H, d, J=2.8 Hz), 8.61 (1H, d, J=5.2Hz), 13.86 (1H, s). [M+H] Calc'd for C₁₀H₉N₃O₂, 204. Found, 204.

Example 32 2-(5-benzyl-1H-pyrazol-1-yl)isonicotinic acid A.1-phenylpropan-2-one

A solution of 1-phenylpropan-2-ol (2.72 g, 20 mmol) in CH₂Cl₂ (20 mL)was added pyridinium chlorochromate (PCC, 5.4 g, 25 mmol) at 0° C. andthe mixture was stirred for 3 h. The mixture was concentrated andpurified by flash column chromatography (PE/EtOAc=20:1) to give thetitle compound (2.3 g, 84%) as a yellow oil.

B. (3E)-4-hydroxy-1-phenylbut-3-en-2-one

To a solution of 1-phenylpropan-2-one (1.78 g, 13 mmol) in anhydrousdiethyl ether (50 ml) containing sodium cut in small pieces (299 mg, 13mmol), ethyl formate (1.4 g, 20 mmol) was added slowly with stirring andice-cooling. After standing overnight at rt, water was added, and theether layer was washed with water. The organic phase was dried,concentrated, and purified by flash column chromatography(PE/EtOAc=10:1) to give the title compound (1.2 g, 57%) as a yellow oil.

C. (3E)-4-(dimethylamino)-1-phenylbut-3-en-2-one

A solution of (3E)-4-hydroxy-1-phenylbut-3-en-2-one (1.2 g, 7.4 mmol) inTHF (20 mL) was added dimethylamine hydrochloride (1.8 g, 22.2 mmol),K₂CO₃ (6.1 g, 44.4 mmol) and the mixture was stirred at rt overnight.The mixture was concentrated and purified by flash column chromatography(PE/EtOAc=10:1) to give the title compound (0.6 g, 43%) as a yellow oil.[M+H] Calc'd for C₁₂H₁₅NO, 190. Found, 190.

D. 2-(5-benzyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (32-d1) and2-(3-benzyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (32-d2)

A mixture of 2-hydrazinylisonicotinonitrile (268 mg, 2 mmol, PREPARATION2) and (3E)-4-(dimethylamino)-1-phenylbut-3-en-2-one (567 mg, 3 mmol) inEtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. Thereaction mixture was cooled, concentrated, and purified by prep-HPLC toafford compound 32-d1 (100 mg) and compound 32-d2 (110 mg).

32-d1: [M+H] Calc'd for C₁₆H₁₂N₄, 261. Found, 261.

32-d2: [M+H] Calc'd for C₁₆H₁₂N₄, 261. Found, 261.

E. 2-(5-benzyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 57% yield from2-(5-benzyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (32-d1) according tothe procedure for the preparation of Example 28, part E. ¹H NMR (300MHz, DMSO-d₆): δ 4.03 (2H, s), 6.40 (1H, d, J=2.4 Hz), 7.21-7.25 (1H,m), 7.27-7.32 (4H, m), 7.70 (1H, dd, J=4.8, 1.2 Hz), 8.27 (1H, s), 8.54(1H, d, J=2.4 Hz), 8.60 (1H, d, J=5.4 Hz). [M+H] Calc'd for C₁₆H₁₃N₃O₂,280. Found, 280.

Example 33 2-(3-benzyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 30% yield from2-(3-benzyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (32-d2) according tothe procedure for the preparation of Example 28, part E. ¹H NMR (300MHz, DMSO-d₆): δ 4.53 (2H, s), 6.19 (1H, s), 7.17-7.27 (5H, m),7.69-7.72 (2H, m), 8.20 (1H, s), 8.60 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₆H₁₃N₃O₂, 280. Found, 280.

Example 34 2-(5-phenethyl-1H-pyrazol-1-yl)isonicotinic acid A.(1E)-1-(dimethylamino)-5-phenylpent-1-en-3-one

A solution of 4-phenylbutan-2-one (3.96 g, 20 mmol) and DMF-DMA (2.4 g,20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reactionmixture was cooled, concentrated, and purified by silica gel column(PE/EA=4:1-2:1) to give the title compound (1.5 g, 37%) as a yellow oil.

B. 2-[5-(2-phenylethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (34-b1)and 2-[3-(2-phenylethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (34-b2)

A mixture of 2-hydrazinylisonicotinonitrile (268 mg, 2 mmol, PREPARATION2) and (1E)-1-(dimethylamino)-5-phenylpent-1-en-3-one (406 mg, 2 mmol)in EtOH (5 mL) and AcOH (1 mL) was stirred at 90° C. overnight. Thereaction mixture was cooled, concentrated, and purified by prep-HPLC toafford compound 34-b1 (92 mg) and compound 34-b2 (180 mg).

34-b1: [M+H] Calc'd for C₁₇H₁₄N₄, 275. Found, 275.

34-b2: [M+H] Calc'd for C₁₇H₁₄N₄, 275. Found, 275.

C. 2-(5-phenethyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 46% yield from2-[5-(2-phenylethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (34-b1)according to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.95-3.03 (4H, m), 6.46 (1H, d, J=2.4 Hz),7.16-7.21 (1H, m), 7.26-7.29 (4H, m), 7.70 (1H, dd, J=4.2, 1.2 Hz), 8.26(1H, s), 8.53 (1H, d, J=2.4 Hz), 8.61 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₇H₁₅N₃O₂, 294. Found, 294.

Example 35 2-(3-phenethyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 61% yield from2-[3-(2-phenylethyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (34-b2)according to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.93 (2H, t, J=7.6 Hz), 3.41 (2H, t, J=7.6Hz), 6.41 (1H, s), 7.15-7.29 (5H, m), 7.70 (1H, d, J=1.6 Hz), 7.75 (1H,dd, J=4.2, 1.6 Hz) 8.23 (s, 1H), 8.69 (1H, d, J=4.2 Hz), 13.86 (1H, br).[M+H] Calc'd for C₁₇H₁₅N₃O₂, 294. Found, 294.

Example 36 2-(5-methyl-4-phenyl-1H-pyrazol-1-yl)isonicotinic acid A.(3E)-4-(dimethylamino)-3-phenylbut-3-en-2-one

A solution of 1-phenylpropan-2-one (2.3 g, 20 mmol) and DMF-DMA (2.4 g,20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reactionmixture was cooled, concentrated, and purified by silica gel column(PE/EtOAc=4:1-2:1) to give the title compound (0.7 g, 18%) as a yellowoil.

B. 2-(5-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 34% yield from(3E)-4-(dimethylamino)-3-phenylbut-3-en-2-one and2-hydrazinylisonicotinonitrile (PREPARATION 2) according to theprocedure for the preparation of Example 28, part D. [M+H] Calc'd forC₁₆H₁₂N₄, 261. Found, 261.

C. 2-(5-methyl-4-phenyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 41% yield from2-(5-methyl-4-phenyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 2.72 (3H, s), 7.32-7.36 (1H, m), 7.45-7.51 (4H, m),7.79 (1H, dd, J=4.8, 1.2 Hz), 7.98 (1H, s), 8.29 (1H, s), 8.71 (1H, d,J=4.8 Hz), 13.90-13.91 (1H, broad). [M+H] Calc'd for C₁₆H₁₃N₃O₂, 280.Found, 280.

Example 37 2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)isonicotinic acid A.2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

A mixture of 2-hydrazinylisonicotinonitrile (536 mg, 4 mmol, PREPARATION2) and ethyl 3-oxobutanoate (780 mg, 6 mmol) in EtOH (10 mL) and AcOH (2mL) was stirred at 90° C. overnight. The reaction mixture was cooled,concentrated, and purified by flash column chromatography (CH₂Cl₂) toafford the title compound (500 mg, 67%) as a yellow solid. [M+H] Calc'dfor C₁₀H₈N₄O, 201. Found, 201.

B. 2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile

To a solution of2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (200 mg, 1mmol) and K₂CO₃ (276 mg, 2 mmol) in DMF was added MeI (213 mg, 1.5 mmol)dropwise at −20° C. The mixture was warmed to 0° C. and stirred for 3 h.Water was added, and the reaction mixture was extracted with EtOAc, thenwashed with water and brine. The organic phase was dried, concentrated,and purified by prep-HPLC to afford the title compound (50 mg). [M+H]Calc'd for C₁₁H₁₀N₄O, 215. Found, 215.

C. 2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 81% yield from2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 2.19 (3H, s), 4.33 (3H, s), 5.78 (1H, s), 7.69 (1H, d,J=4.4 Hz), 8.04 (1H, s), 8.63 (1H, d, J=5.2 Hz). [M+H] Calc'd forC₁₁H₁₁N₃O₃, 234. Found, 234.

Example 38 2-(5-(benzyloxy)-3-methyl-1H-pyrazol-1-yl)isonicotinic acidA. 2-[5-(benzyloxy)-3-methyl-1H-pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (300 mg,1.5 mmol) and K₂CO₃ (518 mg, 3.75 mmol) in DMF was added benzyl bromide(308 mg, 1.8 mmol) dropwise at −20° C., then the mixture was warmed to0° C. and stirred for 3 h. Water was added, and the reaction mixture wasextracted with EtOAc, then washed with water and brine. The organicphase was dried, concentrated, and purified by prep-HPLC to afford thetitle compound (20 mg). [M+H] calc'd for C₁₇H₁₄N₄O 291. Found, 291.

B. 2-(5-(benzyloxy)-3-methyl-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 29% yield from2-[5-(benzyloxy)-3-methyl-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, CD₃OD): δ 2.23 (3H, s), 5.26 (2H, s), 5.73 (1H, s),7.30-7.38 (3H, s), 7.44-7.46 (2H, m), 7.74 (1H, d, J=4.8 Hz), 8.18 (1H,s), 8.49 (1H, d, J=4.4 Hz). [M+H] Calc'd for C₁₇H₁₅N₃O₃, 310. Found,310.

Example 39 2-(5-(benzyloxy)-1H-pyrazol-1-yl)isonicotinic acid A. ethyl(2E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]prop-2-enoate

To a solution of 2-hydrazinylisonicotinonitrile (500 mg, 3.73 mmol,PREPARATION 2) and ethyl (2E)-3-(dimethylamino)prop-2-enoate (534 mg,3.73 mmol) in 20 mL EtOH was added 4 mL AcOH, before the mixture washeated under reflux conditions overnight. The reaction mixture wascooled and concentrated to dryness. The residue was adjusted to pH>8with sat′d. aq. NaHCO₃ and extracted with EtOAc. The combined organiclayers were washed with brine, dried, and concentrated to dryness. Theresidue was purified by flash column chromatography (PE/EtOAc=5/1) togive the title compound (300 mg, 35%) as a yellow solid. [M+H] Calc'dfor C₁₁H₁₂N₄O₂, 233. Found, 233.

B. 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile

To a solution of ethyl(2E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]prop-2-enoate (2.0 g, 8.62mmol) in 30 mL EtOH was added t-BuOK (1.93 g, 17.24 mmol) at 0-5° C. Themixture was stirred for 3 days at rt. The mixture was adjusted to pH=6with 1 N HCl with cooling. The mixture was extracted with EtOAc (3×100mL). The organic layers were washed with 200 ml brine, dried overNa₂SO₄, and concentrated to dryness. The resultant residue was stirredwith PE/EtOAc (10/10 mL) for 30 min and filtered to give the titlecompound (500 mg, 31%) as a red solid. ¹H NMR (400 MHz, CDCl₃): δ 4.63(1H, s), 7.12 (1H, dd, J=4.8, 1.2 Hz), 7.16 (1H, s), 8.35 (1H, d, J=4.4Hz), 8.43 (1H, s). [M+H] Calc'd for C₉H₆N₄O, 187. Found, 187.

C. 2-[5-(benzyloxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile(186 mg, 1 mmol), phenylmethan-1-ol (216 mg, 2 mmol), and PPh₃ (523 mg,2 mmol) in THF (10 mL) was added dropwise DIAD (402 mg, 2 mmoL) at 0° C.under N₂. Then the mixture was stirred at rt overnight. Water was added,and the reaction mixture was extracted with EtOAc, then washed withwater and brine. The organic phase was dried, concentrated, and purifiedby prep-HPLC to afford the title compound (60 mg). ¹H NMR (400 MHz,CDCl₃): δ 5.25 (2H, s), 5.75 (1H, d, J=2.0 Hz), 7.36-7.44 (5H, m), 7.57(1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₆H₁₂N₄O, 277. Found, 277.

D. 2-(5-(benzyloxy)-1H-pyrazol-1-yl)isonicotinic acid

The title compound was prepared in 31% yield from2-[5-(benzyloxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrile according tothe procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 5.28 (2H, s), 5.92 (1H, br), 7.24-7.29 (3H, m),7.30-7.32 (2H, m), 7.39-7.42 (1H, m), 7.56 (1H, br), 8.24 (1H, s), 8.60(1H, s). [M+H] Calc'd for C₁₆H₁₃N₃O₃, 296. Found, 296.

Example 402-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

To a mixture of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile(185 mg, 0.99 mmol), 4-fluorobenzyl alcohol (188 mg, 1.49 mol), PPh₃(391 mg, 1.49 mmol) and THF (4 mL) cooled in an ice-water bath, TMAD(257 mg, 1.49 mmol) was added. The reaction mixture was stirredovernight at rt, filtered, and concentrated before purification byprep-HPLC to give the title compound (40 mg, 13%). ¹H NMR (400 MHz,CDCl₃): δ 5.14 (2H, s), 5.68 (1H, s), 7.00-7.05 (2H, m), 7.33-7.36 (3H,m), 7.52 (1H, s), 7.96 (1H, s), 8.64 (1H, s). [M+H] Calc'd forC₁₆H₁₁FN₄O, 295. Found, 295.

B. 2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared in 47% yield from2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.27 (2H, s), 6.01 (1H, d, J=2.0 Hz),7.19-7.24 (2H, m), 7.52-7.60 (3H, m), 7.76 (1H, d, J=4.8 Hz), 8.08 (1H,s), 8.68 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₆H₁₂FN₃O₃, 313. Found,313.

Example 412-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 27% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-fluorobenzylalcohol according to the procedure for the preparation of Example 39,part C. ¹H NMR (400 MHz, CDCl₃): δ 5.24 (2H, s), 5.73 (1H, d, J=2.0 Hz),7.03-7.05 (1H, m), 7.07-7.21 (2H, m), 7.36-7.38 (1H, m), 7.40-7.42 (1H,m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=4.2 Hz). [M+H]Calc'd for C₁₆H₁₁FN₄O, 295. Found, 295.

B. 2-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared in 50% yield from2-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.20 (2H, s), 5.86 (1H, s), 6.93-6.98 (1H, m),7.13-7.19 (2H, m), 7.26-7.31 (1H, m), 7.49 (1H, d, J=1.2 Hz), 7.75 (1H,d, J=4.8 Hz), 8.18 (1H, s), 8.56 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₁₆H₁₂FN₃O₃, 313. Found, 313.

Example 422-{5-[(3-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidA. 2-{5-[(3-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 13% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-methoxybenzylalcohol according to the procedure for the preparation of Example 39,part C. [M+H] Calc'd for C₁₇H₁₄N₄O₂, 307. Found, 307.

B. 2-{5-[(3-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared in 22% yield from2-{5-[(3-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.75 (3H, s), 5.26 (2H, s), 6.01 (1H, d, J=2.0Hz), 6.85-6.87 (1H, m), 7.04-7.07 (2H, m), 7.27-7.29 (1H, m), 7.60 (1H,d, J=2.0 Hz), 7.77 (1H, d, J=4.8 Hz), 8.09 (1H, s), 8.70 (1H, d, J=5.2Hz). [M+H] Calc'd for C₁₇H₁₅N₃O₄, 326. Found, 326.

Example 432-{5-[(4-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidA. 2-{5-[(4-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 14% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 4-methoxybenzylalcohol according to the procedure for the preparation of Example 39,part C. ¹H NMR (400 MHz, CDCl₃): δ 3.81 (3H, s), 5.17 (2H, s), 5.75 (1H,d, J=2.0 Hz), 6.91-6.93 (2H, m), 7.34-7.39 (3H, m), 7.57 (1H, d, J=2.0Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₄N₄O₂,307. Found, 307.

B. 2-{5-[(4-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared in 62% yield from2-{5-[(4-methoxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, CD₃OD): δ 3.82 (3H, s), 5.24 (2H, s), 5.99 (1H, d, J=2.0Hz), 6.93-6.95 (2H, m), 7.41-7.43 (2H, m), 7.61 (1H, d, J=2.0 Hz), 7.86(1H, d, J=5.2 Hz), 8.28 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₇H₁₅N₃O₄, 326. Found, 326.

Example 44 2-(5-butyl-1H-pyrazol-1-yl)pyridine-4-carboxylic acid A.(1E)-1-(dimethylamino)hept-1-en-3-one

A solution of 2-hexanone (2.0 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol)in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixturewas cooled, concentrated, and purified by flash column chromatography(PE/EtOAc=4:1-2:1) to give the title compound (0.6 g, 19%) as yellowoil.

B. 2-(5-butyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (44-b1) and2-(3-butyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (44-b2)

A mixture of 2-hydrazinylisonicotinonitrile (268 mg, 2 mmol, PREPARATION2) and (1E)-1-(dimethylamino)hept-1-en-3-one (310 mg, 2 mmol) in EtOH (5mL) and AcOH (1 mL) was stirred at 90° C. overnight. The reactionmixture was cooled, concentrated, and purified by prep-HPLC to affordcompound 44-b1 (60 mg) and compound 44-b2 (100 mg).

44-b1: [M+H] Calc'd for C₁₃H₁₄N₄, 227. Found, 227.

44-b2: [M+H] Calc'd for C₁₃H₁₄N₄, 227. Found, 227.

C. 2-(5-butyl-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

The title compound was prepared in 34% yield from2-(5-butyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (44-b1) according tothe procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 0.92 (3H, t, J=7.6 Hz), 1.34-1.40 (2H, m), 1.61-1.67(2H, m), 2.66 (2H, t, J=7.6 Hz), 6.45 (1H, d, J=2.4 Hz), 7.69-7.71 (1H,m), 8.25 (1H, s), 8.52 (1H, d, J=2.8 Hz), 8.61 (1H, d, J=5.2 Hz). [M+H]Calc'd for C₁₃H₁₅N₃O₂, 246. Found, 246.

Example 45 2-(3-butyl-1H-pyrazol-1-yl)pyridine-4-carboxylic acid

The title compound was prepared in 55% yield from2-(3-butyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (44-b2) according tothe procedure for the preparation of Example 28, part E. ¹H NMR (400MHz, DMSO-d₆): δ 0.89 (3H, t, J=7.6 Hz), 1.32-1.38 (2H, m), 1.57-1.61(2H, m), 3.11 (2H, t, J=7.6 Hz), 6.36 (1H, d, J=0.8 Hz), 7.68 (1H, d,J=1.6 Hz), 7.74-7.76 (1H, m), 8.25 (1H, s), 8.66 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₃H₁₅N₃O₂, 246. Found, 246.

Example 46 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylicacid A. (2E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one

A solution of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) in DMF-DMA (25mL) was stirred at 100° C. for 16 h. The solution was concentrated andpurified by flash column chromatography (hexanes:EtOAc=4:1˜2:1) to givethe title compound (1.57 g, 61%) as an orange-brown solid.

B. 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

A solution of (2E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one(100 mg, 0.39 mmol) and 2-hydrazinylpyridine-4-carbonitrilehydrochloride salt (90 mg, 0.43 mmol, PREPARATION 3) in MeOH (10 mL) washeated under reflux conditions for 30 min and then cooled to rt. Thesolution was concentrated, and the residue was purified by flash columnchromatography (hexanes:EtOAc=1:1) to give the title compound (108 mg,85%) as an orange-yellow solid.

C. 2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

To a solution of2-[5-(4-bromophenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (100 mg,0.31 mmol) in MeOH (4 mL) was added 10 N NaOH (4 mL), and the solutionwas heated under reflux conditions for 1 h. The solution was then cooledto 0° C. and the pH was adjusted to pH=2 by dropwise addition of 12 NHCl. The resulting precipitate was filtered to give the title compound(92 mg, 87%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD): δ 6.64 (1H,s), 7.16 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.8 Hz), 7.79 (1H, s), 7.84(1H, d, J=8.4 Hz), 8.13 (1H, s), 8.42 (1H, d, J=8.4 Hz). [M+H] Calc'dfor C₁₅H₁₀BrN₃O₂, 344. Found, 344.

Example 472-{5-[4-(dimethylamino)phenyl]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.(2E)-3-(dimethylamino)-1-[4-(dimethylamino)phenyl]prop-2-en-1-one

A solution of 1-[4-(dimethylamino)phenyl]ethanone (500 mg, 3.1 mmol) inDMF-DMA (10 mL), toluene (10 mL), and AcOH (2 drops), was heated underreflux conditions for 48 h. The solution was concentrated and purifiedby flash column chromatography (hexanes:EtOAc=8:2˜1:1) to give the titlecompound (121 mg, 18%) as a yellow solid.

B.2-{5-[4-(dimethylamino)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 69% yield from2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3)and (2E)-3-(dimethylamino)-1-[4-(dimethylamino)phenyl]prop-2-en-1-oneaccording to the procedure for the preparation of Example 46, part B.

C. 2-{5-[4-(dimethylamino)phenyl]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared in 47% yield from2-{5-[4-(dimethylamino)phenyl]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 46, part B. ¹HNMR (400 MHz, DMSO-d₆): δ 2.88 (6H, s), 6.53 (1H, s), 6.63 (2H, d, J=16Hz), 7.06 (2H, d, J=16 Hz), 7.73 (1H, s), 7.77 (1H, d, J=8 Hz), 8.00(1H, s), 8.48 (1H, d, J=8 Hz). [M+H] Calc'd for C₁₇H₁₆N₄O₂, 309. Found,309.

Example 482-[3-amino-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylic acidA. methyl 4-(4-methylphenyl)-2,4-dioxobutanoate

Sodium (1.0 g, 43 mmol) was dissolved in MeOH (50 mL) and thenevaporated to a dry white powder. To the powder was added MTBE (100 mL)and diethyloxalate (5.14 g, 35.2 mmol). To the resulting solution wasadded a solution of 1-(4-methylphenyl)ethanone (5.0 g, 37.3 mmol) inMTBE (50 mL) dropwise over 45 min. The resulting suspension was allowedto stir for 1 h, and the precipitate was filtered and washed withMTBE/hexanes (1:1, 50 mL). The solid was suspended in 1 N HCl (100 mL)and extracted with EtOAc (2×100 mL). The combined extracts were dried(MgSO₄), filtered, and concentrated to an oily residue whichcrystallized on standing at rt. The yellow solid was triturated withMTBE/hexanes (1:1) and filtered to give the title compound (3.76 g, 46%)as a white solid.

B. methyl1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate

A solution of methyl 4-(4-methylphenyl)-2,4-dioxobutanoate (500 mg, 22.7mmol) and 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (500mg, 24.2 mmol, PREPARATION 3) in AcOH (10 mL) was heated at 100° C. for30 min and cooled to rt. The solution was concentrated to an oilyresidue which was partitioned between EtOAc (50 mL) and water (50 mL).The pH was adjusted to pH=8 using a saturated aq. Na₂CO₃ solution. Theorganics were dried (MgSO₄), filtered, and concentrated to give a solidwhich was triturated with MTBE/hexanes (1:1) and filtered to give thetitle compound (613 mg, 85%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD):δ 2.48 (3H, s), 3.92 (3H, s), 7.01 (1H, s), 7.08-7.21 (4H, m), 7.71 (1H,d, J=4.8 Hz), 8.12 (1H, s), 8.48 (1H, d, J=4.8 Hz), 8.00 (1H, s), 8.48(1H, d, J=8 Hz).

C. 1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazole-3-carboxylicacid

A solution of methyl1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate(500 mg, 1.57 mmol) in DMF/THF (1:1, 15 mL) was heated to 65° C. andNaOH (628 mg, 15.7 mmol) in water (1 mL) was added. The resultingsolution was stirred at 65° C. and monitored by TLC. The reaction wascooled to rt at the point where a second more polar eluting product(relative to the product spot) began to form. The pH of the solution wasadjusted to pH=4 with 6 N HCl, and the reaction mixture was extractedwith EtOAc (2×50 mL). The organic layers were combined, washed withwater (2×50 mL), dried (MgSO₄), filtered, concentrated, and purified byflash column chromatography (EtOAc:hexanes=40:60) to give the titlecompound (196 mg, 41%).

D. tert-Butyl[1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazol-3-yl]carbamate

To a solution of1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazole-3-carboxylic acid(190 mg, 0.63 mmol) in THF (5 mL) at 0° C. was added isobutylchloroformate (93.8 mg, 0.69 mmol) followed by dropwise addition of asolution of TEA (76.4 mg, 0.76 mmol) in THF (0.5 mL). The resultingsuspension was allowed to stir at rt for 1 h before NaN₃ (203 mg, 3.12mmol) in water (1 mL) was added. The solution was stirred an additionalhour. The solution was diluted with water (20 mL) and extracted withEtOAc (2×20 mL). The organic layers were dried (MgSO₄), filtered, andconcentrated, and the residue dissolved in tert-butyl alcohol (20 mL).The solution was heated at 75° C. for 4 h until TLC indicated therearrangement reaction to be complete. The solution was diluted withwater (10 mL) and extracted with EtOAc (2×20 mL). The organic layerswere dried (MgSO₄), filtered, concentrated, and purified by flash columnchromatography (EtOAc/hexanes=30:70) to give the title compound (152 mg,65%) as a white solid.

E. 2-[3-amino-5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carboxylicacid

A solution oftert-butyl[1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazol-3-yl]carbamate(150 mg, 0.4 mmol) in TFA (2 mL) was heated to 50° C. for 30 min andevaporated to an oily residue. To the residue was added 10 N NaOH (2 mL)followed by MeOH (2 mL). The solution was stirred at 70° C. for 4 h andthen cooled to rt. Solvent was evaporated, and the pH of the resultingaqueous phase was carefully adjusted to pH=5.5 using conc. HCl and then1 N HCl. The resulting mixture was extracted with EtOAc (2×20 mL). Theorganic layers were dried (MgSO₄), filtered, concentrated to an oil, andpurified by flash column chromatography (MeOH/EtOAc=5:95) to give thetitle compound (56 mg, 48%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆):δ 2.28 (3H, s), 5.73 (1H, s), 5.82 (1H, s), 7.05-7.18 (4H, m), 7.51 (1H,d, J=5.2 Hz), 8.02 (1H, s), 8.22 (1H, d, J=5.2 Hz). [M+H] Calc'd forC₁₆H₁₄N₄O₂, 295. Found, 295.

Example 492-[5-(1H-indazol-6-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylic acidA. 1-tert-Butyl, 6-methyl 1H-indazole-1,6-dicarboxylate

To an ice-cooled solution of methyl 1H-indazole-6-carboxylate (502 mg,2.84 mmol), DMAP (69 mg, 0.57 mmol) and Et₃N (431 mg, 4.26 mmol) in THF(10 mL) was added Boc₂O (743 mg, 3.41 mmol) slowly. The reaction mixturewas stirred overnight at room temperature. It was then concentrated, theresidue was extracted with ethyl acetate, collected the organic phase,concentrated for gel chromatograph to provide 797 mg of the titlecompound (100%). ¹H NMR (400 MHz, CDCl₃): δ 1.74 (9H, s), 3.97 (3H, s),7.77 (1H, dd, J=0.4 Hz, J=8.4 Hz), 7.95 (1H, dd, J=1.2 Hz, J=8.4 Hz),8.21 (1H, d, J=0.8 Hz), 8.90 (1H, s). [M+H] Calc'd for C₁₄H₁₆N₂O₄, 277,221, 177. Found, 221.

B. tert-butyl 6-(hydroxymethyl)-1H-indazole-1-carboxylate

A solution of 1-tert-butyl 6-methyl 1H-indazole-1,6-dicarboxylate (766mg, 2.76 mmol) in anhydrous THF (11 mL) was cooled to −30° C., LiAlH₄(210 mg, 5.53 mmol) was added in portions below −30° C., and the mixturewas stirred at this temperature for 1.5 h, added water:10%NaOH:water=0.8 mL:2.4 mL:0.8 mL carefully, filtered, and the filtratewas concentrated and purified by silica gel chromatograph to afford 100mg of the title compound (14%). ¹H NMR (400 MHz, CDCl₃): δ 1.72 (9H, s),4.86 (2H, s), 7.33 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=8.4 Hz), 8.13 (1H,s), 8.21 (1H, s). [M+H] Calc'd for C₁₃H₁₆N₂O₃, 249. Found, 249.

C. tert-butyl5-((1-(4-cyanopyridin-2-yl)-1H-pyrazol-5-yloxy)methyl)-1H-indazole-1-carboxylate

The title compound was prepared in 17% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and tert-butyl6-(hydroxymethyl)-1H-indazole-1-carboxylate according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl3): δ1.71 (9H, s), 5.41 (2H, s), 5.78 (1H, d, J=1.6 Hz), 7.37-7.42 (2H, m),7.57 (1H, d, J=1.6 Hz), 7.76 (1H, d, J=8.0 Hz), 8.07 (1H, s), 8.17 (1H,s), 8.41 (1H, s), 8.78 (1H, d, J=8.4 Hz). [M+H] Calc'd for C₂₂H₂₀N₆O₃,417. Found, 417.

D. 2-[5-(1H-indazol-6-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylicacid

To a solution of tert-butyl5-((1-(4-cyanopyridin-2-yl)-1H-pyrazol-5-yloxy)methyl)-1H-indazole-1-carboxylate(65 mg, 0.15 mmol) in ethyl acetate (2 mL) was added HCl in EtOAc (5 mL)and the mixture was stirred for 2 h. Solvent was removed and the residuewas dissolved with ethanol (2 mL), NaOH (2.5 mL, 5M) was added, themixture was then stirred for 6 h at 90° C. Cooled to 0° C., and thesolution was acidified with HCl (2N) (pH=4), filtered, the solid waspurified by HPLC to afford 8 mg of the title compound (15%). ¹H NMR (400MHz, CD₃OD): δ 3.86 (2H, s), 4.91 (1H, s), 7.15 (1H, d, J=8.0 Hz), 7.45(1H, s), 7.55 (1H, s), 7.71 (1H, d, J=8.0 Hz), 7.78 (1H, d, J=4.8 Hz),7.99 (1H, s), 8.59 (1H, d, J=4.8 Hz), 8.83 (1H, s). [M+H] Calc'd forC₁₇H₁₃N₅O₃, 336. Found, 336.

Preparation 4 Methyl 1-methyl-1H-indazole-6-carboxylate and methyl2-methyl-2H-indazole-6-carboxylate

To an ice-cooled solution of methyl 1H-indazole-6-carboxylate (566 mg,3.21 mmol) was added NaH (154 mg, 3.85 mmol), the mixture was thenstirred at room temperature for 30 min. Methyl iodide (547 mg, 3.85mmol) was added drop wise, and the reaction mixture was stirredovernight. Cooled to 0° C., added water and extracted with ethylacetate. The organic phase was concentrated and purified by gelchromatograph to provide 130 mg of methyl1-methyl-1H-indazole-6-carboxylate and 230 mg of methyl2-methyl-2H-indazole-6-carboxylate, 59%. ¹H NMR for methyl1-methyl-1H-indazole-6-carboxylate: ¹H NMR (400 MHz, CDCl₃): δ 3.97 (3H,s), 4.14 (3H, s), 7.74-7.82 (2H, m), 8.02 (1H, s), 8.17 (1H, d, J=0.8Hz). ¹H NMR for methyl 2-methyl-2H-indazole-6-carboxylate: ¹H NMR (400MHz, CDCl3): δ 3.94 (3H, s), 4.25 (3H, s), 7.65-7.72 (2H, m), 7.92 (1H,s), 8.47 (1H, d, J=1.2 Hz). [M+H] Calc'd for C₁₀H₁₀N₂O₂, 191. Found,191.

Example 502-{5-[(1-methyl-1H-indazol-6-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A. (1-methyl-1H-indazol-6-yl)methanol

A solution of methyl 1-methyl-1H-indazole-6-carboxylate (230 mg, 1.21mmol, PREPARATION 4) in anhydrous THF (4 mL) was cooled to 0° C., LiAlH₄(92 mg, 2.42 mmol) was added in portions below 0° C., and the mixturewas then stirred at 0° C. for 1.5 h, added water: 10% NaOH:water=0.2 mL:0.2 mL: 0.6 mL carefully, filtered, and the filtrate was concentratedand purified by silica gel flash column to give 192 mg of crude productwhich was used directly for next step (98%). [M+H] Calc'd for C₉H₁₀N₂O,163. Found, 163.

B.2-{5-[(1-methyl-1H-indazol-6-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 11% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(1-methyl-1H-indazol-6-yl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 4.09 (3H,s), 5.40 (2H, s), 5.78 (1H, d, J=1.6 Hz), 7.19-7.17 (1H, m), 7.40 (1H,dd, J=1.2 Hz, J=5.2 Hz), 7.51 (1H, s), 7.58 (1H, d, J=2.0 Hz), 7.75 (1H,s, J=8.4 Hz), 7.99 (1H, d, J=0.4 Hz), 8.07 (1H, s), 8.71 (1H, d, J=8.4Hz). [M+H] Calc'd for C₁₈H₁₄N₆O, 331. Found, 331.

C.2-{5-[(1-methyl-1H-indazol-6-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared in 45% yield from2-{5-[(1-methyl-1H-indazol-6-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 4.03 (3H, s), 5.42 (2H, s), 6.07 (1H, d, J=1.6Hz), 7.22 (1H, dd, J=0.8 Hz, J=8.4 Hz), 7.60 (1H, d, J=1.6 Hz),7.75-7.78 (3H, m), 8.04 (1H, s), 8.11 (1H, s), 8.71 (1H, d, J=4.8 Hz),13.86 (1H, d, J=4.0 Hz). [M+H] Calc'd for C₁₅H₁₅N₅O₃, 350. Found, 350.

Example 512-{5-[(2-methyl-2H-indazol-5-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A. (2-methyl-2H-indazol-6-yl)methanol

The title compound was prepared in 71% yield from methyl2-methyl-2H-indazole-6-carboxylate according to the procedure for thepreparation of Example 50, part A. [M+H] Calc'd for C₉H₁₀N₂O, 163.Found, 163.

B.2-{5-[(2-methyl-2H-indazol-5-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared in 23% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-methyl-2H-indazol-6-yl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, DMSO-d₆): δ 4.16(3H, s), 5.35 (2H, s), 6.05 (1H, d, J=2.0 Hz), 7.11 (1H, dd, J=2.0 Hz,J=8.4 Hz), 7.61 (1H, d, J=2.4 Hz), 7.68-7.71 (2H, m), 7.81 (1H, dd,J=1.2 Hz, J=5.2 Hz), 8.07 (1H, s), 8.32 (1H, s), 8.75 (1H, dd, J=0.4 Hz,J=3.2 Hz). [M+H] Calc'd for C₁₈H₁₄N₆O, 331. Found, 331.

C.2-{5-[(2-methyl-2H-indazol-5-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared in 45% yield from2-{5-[(2-methyl-2H-indazol-5-yl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 4.15 (3H, s), 5.34 (2H, s), 6.04 (1H, d, J=1.6Hz), 7.11 (1H, dd, J=1.2 Hz, J=8.8 Hz), 7.58 (1H, d, J=1.6 Hz), 7.68(1H, d, J=8.8 Hz), 7.71 (1H, s), 7.75 (1H, dd, J=1.2 Hz, J=4.8 Hz), 8.08(1H, s), 8.32 (1H, s), 8.68 (1H, d, J=4.8 Hz), 13.84 (1H, s). [M+H]Calc'd for C₁₈H₁₅N₅O₃, 350. Found, 350.

Example 522-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3,4-difluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.19 (2H,s), 5.73 (1H, d, J=2.0 Hz), 7.16-7.34 (3H, m), 7.41-7.42 (1H, m), 7.57(1H, s, J=2.0 Hz), 8.04 (1H, s), 8.70 (1H, s, J=4.4 Hz). [M+H] Calc'dfor C₁₆H₁₀F₂N₄O, 313. Found, 313.

B. 2-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.28 (2H, s), 6.02 (1H, d, J=2.0 Hz),7.35-7.37 (1H, m), 7.43-7.50 (1H, m), 7.55-7.61 (2H, m), 7.76 (1H, dd,J=1.2 Hz, J=5.2 Hz), 8.08 (1H, s), 8.69 (1H, d, J=5.2 Hz), 13.90 (1H, d,J=1.6 Hz). [M+H] Calc'd for C₁₆H₁₁F₂N₃O₃, 332. Found, 332.

Example 532-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chlorophenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.21 (2H, s), 6.72(1H, d, J=2.0 Hz), 7.26 (1H, s), 7.37-7.47 (4H, m), 7.56 (1H, d, J=2.0Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.8 Hz) [M+H] Calc'd for C₁₆H₁₁ClN₄O,311. Found, 311.

B. 2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (300 MHz, DMSO-d₆): δ 5.28 (2H, s), 6.00 (1H, d, J=1.8 Hz),7.42-7.57 (4H, m), 7.60 (1H, d, J=1.8 Hz), 7.75-7.76 (1H, m), 8.08 (1H,s), 8.68 (1H, t, J=4.8 Hz), 13.89 (1H, d, J=3.6 Hz). [M+H] Calc'd forC₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 542-(5-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylicacid A.2-(5-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-(trifluoromethyl)phenyl]methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.31 (2H,s), 5.73 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.55-7.57(3H, m), 7.66-7.68 (2H, m), 8.05 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H]Calc'd for C₁₇H₁₁F₃N₄O, 345. Found, 345.

B.2-(5-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylicacid

The title compound was prepared from2-(5-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.41 (2H, s), 6.01 (1H, d, J=1.6 Hz), 7.61(1H, d, J=1.6 Hz), 7.70-7.78 (5H, m), 8.11 (1H, s), 8.71 (1H, d, J=5.2Hz), 13.90-13.92 (1H, m). [M+H] Calc'd for C₁₇H₁₂F₃N₃O₃, 364. Found,364.

Example 552-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-methylphenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.36 (3H, s), 5.20(2H, s), 5.74 (1H, s, J=1.6 Hz), 7.19-7.32 (4H, m), 7.38 (1H, dd, J=1.2Hz, J=4.8 Hz), 7.56 (1H, s, J=1.2 Hz), 8.02 (1H, s), 8.70 (1H, s, J=4.8Hz). [M+H] Calc'd for C₁₇H₁₄N₄O, 291. Found, 291.

B. 2-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.97 (s, 3H), 5.22 (2H, s), 6.00 (1H, d, J=1.6Hz), 7.18-7.37 (4H, m), 7.58 (1H, d, J=2.0 Hz), 7.75 (1H, dd, J=1.6 Hz,J=5.2 Hz), 8.07 (1H, s), 8.68 (1H, d, J=4.8 Hz), 13.87 (1H, s). [M+H]Calc'd for C₁₇H₁₅N₃O₃, 310. Found, 310.

Example 562-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-ethylphenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.26 (3H, t, J=6.0Hz)), 2.66 (2H, q, J=6.0 Hz), 5.01 (2H, s), 5.75 (1H, d, J=2.0 Hz),7.22-7.35 (4H, m), 7.39 (1H, dd, J=0.8 Hz, J=4.8 Hz), 7.57 (1H, d, J=2.0Hz), 8.02 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₆N₄O,305. Found, 305.

B. 2-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.16 (3H, t, J=8.0 Hz), 2.59 (2H, q, J=8.0Hz), 5.23 (2H, s), 6.00 (1H, d, J=1.6 Hz), 7.21-7.39 (4H, m), 7.58 (1H,d, J=2.0 Hz), 7.74 (1H, dd, J=0.8 Hz, J=4.8 Hz), 8.07 (1H, s), 8.68 (1H,d, J=4.8 Hz), 13.88 (1H, s). [M+H] Calc'd for C₁₈H₁₇N₃O₃, 324. Found,324.

Example 572-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-bromophenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.19 (2H, s), 5.72(1H, s), 7.30-7.32 (2H, m), 7.41 (1H, d, J=0.8 Hz, J=5.2 Hz), 7.52-7.54(2H, m), 7.56 (1H, d, J=0.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.0 Hz).[M+H] Calc'd for C₁₆H₁₁BrN₄O, 355. Found, 355.

B. 2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.27 (2H, s), 6.00 (1H, d, J=2.0 Hz),7.44-7.46 (2H, m), 7.58-7.60 (3H, m), 7.76 (1H, d, J=1.2 Hz, J=4.8 Hz),8.09 (1H, s), 8.69 (1H, d, J=5.2 Hz), 13.90 (1H, s). [M+H] Calc'd forC₁₆H₁₂BrN₃O₃, 374. Found, 374.

Example 582-{5-[(3-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(3-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-chlorophenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.22 (2H, s), 5.73(1H, d, J=1.6 Hz), 7.30-7.35 (3H, m) 7.41-7.43 (1H, m), 7.47 (1H, s),7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.72 (1H, d, J=5.2 Hz). [M+H]Calc'd for C₁₆H₁₁ClN₄O, 311. Found, 311.

B. 2-{5-[(3-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(3-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.31 (2H, s), 6.01 (1H, d, J=1.2 Hz),7.41-7.44 (3H, m), 7.59-7.61 (2H, m), 7.77 (1H, d, J=4.8 Hz), 8.09 (1H,s), 8.70 (1H, d, J=4.8 Hz), 13.90 (1H, s). [M+H] Calc'd forC₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 592-{5-[(2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-fluorophenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.31 (2H, s), 5.81(1H, d, J=1.6 Hz), 7.09-7.20 (2H, m), 7.36-7.41 (2H, m), 7.48-7.51 (1H,m), 7.58 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H]Calc'd for C₁₆H₁₁FN₄O, 295. Found, 295.

B. 2-{5-[(2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (300 MHz, DMSO-d₆): δ 5.33 (2H, s), 6.07 (1H, d, J=1.8 Hz),7.21-7.27 (2H, m), 7.39-7.47 (1H, m), 7.60-7.64 (2H, m), 7.74 (1H, dd,J=1.2 Hz, J=4.8 Hz), 8.08 (1H, s), 8.67 (1H, d, J=2.4 Hz), 13.84 (1H,s). [M+H] Calc'd for C₁₆H₁₂FN₃O₃, 314. Found, 314.

Example 602-[5-(pyridin-3-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid A.2-[5-(pyridin-3-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile andpyridin-3-ylmethanol according to the procedure for the preparation ofExample 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.27 (2H, s), 5.78 (1H,d, J=2.0 Hz), 7.41 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.36 (1H, dd, J=4.8 Hz,J=7.6 Hz), 7.58 (1H, d, J=2.0 Hz), 7.80 (1H, d, J=8.0 Hz), 8.03 (1H, s),8.63 (1H, dd, J=1.2 Hz, J=4.8 Hz), 8.69-8.72 (2H, m). [M+H] Calc'd forC₁₅H₁₁N₅O, 278. Found, 278.

B. 2-[5-(pyridin-3-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared from2-[5-(pyridin-3-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.47 (2H, s), 6.09 (1H, d, J=2.0 Hz), 7.64(1H, d, J=1.6 Hz), 7.78 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.75-7.88 (1H, m),8.11 (1H, s), 8.40 (1H, d, J=8.0 Hz), 8.72 (1H, d, J=5.2 Hz), 8.80 (1H,d, J=5.2 Hz), 8.95 (1H, s), 13.98 (1H, s). [M+H] Calc'd for C₁₅H₁₂N₄O₃,297. Found, 297.

Example 612-[5-(pyridin-4-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid A.2-[5-(pyridin-4-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile andpyridin-4-ylmethanol according to the procedure for the preparation ofExample 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.29 (2H, d, J=9.2 Hz),5.72 (1H, d, J=2.0 Hz), 7.38 (2H, d, J=6.4 Hz), 7.44 (1H, dd, J=1.6 Hz,J=5.2 Hz), 7.57 (1H, d, J=2.0 Hz), 8.09 (1H, s), 8.65 (2H, d, J=5.2 Hz),8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₅H₁₁N₅O, 278. Found, 278.

B. 2-[5-(pyridin-4-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared from2-[5-(pyridin-4-ylmethoxy)-1H-pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.50 (2H, s), 6.01 (1H, d, J=1.6 Hz), 7.63(1H, d, J=2.0 Hz), 7.75 (2H, d, J=6.4 Hz), 7.80 (1H, dd, J=1.2 Hz, J=5.2Hz), 8.15 (1H, s), 8.74-8.75 (3H, m), 13.98 (1H, s). [M+H] Calc'd forC₁₅H₁₂N₄O₃, 297. Found, 297.

Example 62 methyl2-[5-(benzyloxy)-1H-pyrazol-1-yl]pyridine-4-carboxylate

A solution of compound 2-(5-(benzyloxy)-1H-pyrazol-1-yl)isonicotinicacid (32 mg, 011 mmol, 1.0 eq.) in THF was added CH₂N₂ (˜10 eq.), themixture was stirred for 30 min; the solvent was removed to obtain thedesired product (25 mg). ¹H NMR (400 MHz, CDCl₃): δ 3.88 (3H, s), 5.18(2H, s), 5.69 (1H, s), 7.28-7.39 (5H, m), 7.51 (1H, s), 7.69 (1H, d,J=4.4 Hz), 8.28 (1H, s), 8.65 (1H, s). [M+H] Calc'd for C₁₇H₁₅N₃O₃, 310.Found, 310.

Example 63 methyl2-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(3,4-difluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 3.90 (3H, s), 5.12 (2H, s), 5.68 (1H, s),7.09-7.13 (2H, m), 7.24-7.29 (1H, m), 7.52 (1H, s), 7.72 (1H, d, J=4.8Hz), 8.26 (1H, s), 8.65 (1H, s). [M+H] Calc'd for C₁₇H₁₃F₂N₃O₃, 346.Found, 346.

Example 64 Methyl2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 3.89 (3H, s), 5.14 (2H, s), 5.67 (1H, s), 7.28-7.33(4H, m), 7.50 (1H, s), 7.70 (1H, d, J=4.8 Hz), 8.25 (1H, s), 8.63 (1H,s). [M+H] Calc'd for C₁₇H₁₄ClN₃O₃, 344. Found, 344.

Example 65 Methyl2-(5-(4-(trifluoromethyl)benzyloxy)-1H-pyrazol-1-yl)isonicotinate

The title compound was prepared from2-(5-{[4-(trifluoromethyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 3.96 (3H, s), 5.30 (2H, s), 5.75 (1H, s),7.57-7.59 (3H, m), 7.65-7.67 (2H, m), 7.78 (1H, d, J=4.8 Hz), 8.34 (1H,s), 8.71 (1H, s). [M+H] Calc'd for C₁₅H₁₄F₃N₃O₃, 378. Found, 378.

Example 66 Methyl2-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-methylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 2.29 (3H, s), 3.88 (3H, s), 5.13 (2H, s), 5.67 (1H,s), 7.11-7.27 (4H, m), 7.50 (1H, d, J=1.2 Hz), 8.67 (1H, dd, J=0.8 Hz,J=4.8 Hz), 8.26 (1H, s), 8.63 (1H, d, J=4.4 Hz). [M+H] Calc'd forC₁₈H₁₇N₃O₃, 324. Found, 324.

Example 67 Methyl2-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-ethylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 1.17 (3H, t, J=7.6 Hz), 2.59 (2H, q, J=7.6 Hz), 3.88(3H, s), 5.14 (2H, s), 5.68 (1H, d, J=1.2 Hz), 7.14-7.30 (4H, m), 7.50(1H, d, J=1.2 Hz), 7.68 (1H, d, J=5.2 Hz), 8.27 (1H, s), 8.63 (1H, d,J=4.8 Hz). [M+H] Calc'd for C₁₉H₁₉N₃O₃, 338. Found, 338.

Example 68 Methyl2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 3.89 (3H, s), 5.13 (2H, s), 5.67 (1H, s), 7.25-7.46(4H, m), 7.52 (1H, s), 7.71 (1H, d, J=4.8 Hz), 8.26 (1H, s), 8.64 (1H,s). [M+H] Calc'd for C₁₇H₁₄BrN₃O₃, 388. Found, 388.

Example 69 Methyl2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 3.88 (3H, s), 5.14 (2H, s), 5.68 (1H, s), 6.99-7.03(2H, m), 7.34-7.38 (2H, m), 7.51 (1H, s), 7.69 (1H, d, J=4.8 Hz), 8.25(1H, s), 8.63 (1H, s). [M+H] Calc'd for C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 70 Methyl2-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidaccording to the procedure for the preparation of Example 62. ¹H NMR(400 MHz, CDCl₃): δ 3.90 (3H, s), 5.17 (2H, s), 5.68 (1H, s), 6.95-7.00(1H, m), 7.14 (2H, d, J=8.0 Hz), 7.26-7.32 (1H, m), 7.52 (1H, s), 7.72(1H, d, J=5.2 Hz), 8.28 (1H, s), 8.65 (1H, d, J=3.6 Hz). [M+H] Calc'dfor C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 712-{5-[(4,4-difluorocyclohexyl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(4,4-difluorocyclohexyl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4,4-difluorocyclohexyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.40-1.43(2H, m), 1.66-1.74 (2H, m), 1.84-1.88 (3H, m), 2.08-2.11 (2H, m), 3.97(2H, d, J=6.0 Hz), 5.62 (1H, d, J=1.6 Hz), 7.33 (1H, d, J=4.8 Hz), 7.50(1H, d, J=1.6 Hz), 7.94 (1H, s), 8.61 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₆H₁₆F₂N₄O, 319. Found, 319.

B.2-{5-[(4,4-difluorocyclohexyl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(4,4-difluorocyclohexyl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.34-1.37 (2H, m), 1.78-2.04 (7H, m), 4.06(2H, d, J=8.4 Hz), 5.94 (1H, d, J=1.6 Hz), 7.58 (1H, d, J=1.6 Hz), 7.75(1H, dd, J=1.2 Hz, J=4.8 Hz), 8.07 (1H, s), 8.66 (1H, d, J=5.2 Hz),13.89 (1H, s). [M+H] Calc'd for C₁₆H₁₇F₂N₃O₃, 338. Found, 338.

Example 722-{5-[(3-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid A.2-{5-[(3-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-bromophenyl)methanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.22 (2H, s), 5.74(1H, s), 7.28 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=7.6 Hz), 7.42 (1H, d,J=4.4 Hz), 7.49 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=1.2 Hz), 7.64 (1H, s),8.05 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₆H₁₁BrN₄O, 355.Found, 355.

B. 2-{5-[(3-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid

The title compound was prepared from2-{5-[(3-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.30 (2H, s), 6.01 (1H, d, J=1.6 Hz), 7.36(1H, t, J=8.0 Hz), 7.47-7.55 (2H, m), 7.61 (1H, d, J=2.0 Hz), 7.73 (1H,s), 8.77 (1H, dd, J=0.8 Hz, J=4.8 Hz), 8.09 (1H, s), 8.70 (1H, d, J=5.2Hz), 13.89 (1H, s). [M+H] Calc'd for C₁₆H₁₂BrN₃O₃, 374. Found, 374.

Example 732-{5-[(3-hydroxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acidA. 3-({[1-(4-cyanopyridin-2-yl)-1H-pyrazol-5-yl]oxy}methyl)phenylacetate

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and3-(hydroxymethyl)phenyl acetate according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.24 (3H,s), 5.17 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.01-7.03 (1H, m), 7.14 (1H,s), 7.20-7.22 (1H, m), 7.32-7.36 (2H, m), 7.49 (1H, d, J=1.6 Hz), 7.97(1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₄N₄O₃, 335.Found, 335.

B. 2-{5-[(3-hydroxybenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from3-({[1-(4-cyanopyridin-2-yl)-1H-pyrazol-5-yl]oxy}methyl)phenyl acetateaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.20 (2H, s), 5.97 (1H, d, J=1.6 Hz),6.70-6.72 (1H, m), 6.85-6.89 (2H, m), 7.15-7.18 (1H, m), 7.58 (1H, d,J=1.2 Hz), 7.76-7.77 (1H, m), 8.08 (1H, s), 8.70 (1H, d, J=5.2 Hz), 9.48(1H, s), 13.89 (1H, s). [M+H] Calc'd for C₁₆H₁₃N₃O₄, 312. Found, 312.

Example 742-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-3-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.21 (2H,s), 5.72 (1H, d, J=1.6 Hz), 7.15 (1H, d, J=8.0 Hz), 7.28 (1H, dd, J=1.6Hz, J=9.6 Hz), 7.40-7.44 (2H, m), 7.57 (1H, d, J=2.08 Hz), 8.04 (1H, s),8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₆H₁₀ClFN₄O, 329. Found, 329.

B.2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.31 (2H, s), 6.01 (1H, d, J=2.0 Hz), 7.36(1H, d, J=8.4 Hz), 7.55 (1H, dd, J=2.0 Hz, J=10.4 Hz), 7.60-7.64 (2H,m), 8.77 (1H, dd, J=0.8 Hz, J=4.8 Hz), 8.10 (1H, s), 8.70 (1H, d, J=4.8Hz), 13.88 (1H, d, J=3.2 Hz). [M+H] Calc'd for C₁₆H₁₁ClFN₃O₃, 348.Found, 348.

Example 752-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.19 (2H,s), 5.72 (1H, d, J=1.6 Hz), 7.07-7.13 (2H, m), 7.33-7.41 (2H, m), 7.51(1H, d, J=2.0 Hz), 7.95 (1H, s), 8.62 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₆H₁₀ClFN₄O, 329. Found, 329.

B.2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.32 (2H, s), 6.08 (1H, d, J=1.6 Hz), 7.34(1H, dd, J=1.6 Hz, J=8.0 Hz), 7.49 (1H, dd, J=2.0 Hz, J=9.6 Hz),7.61-7.68 (2H, m), 7.75 (1H, dd, J=1.6 Hz, J=5.2 Hz), 8.05 (1H, s), 8.67(1H, d, J=5.2 Hz), 13.89 (1H, s). [M+H] Calc'd for C₁₆H₁₁ClFN₃O₃, 348.Found, 348.

Example 762-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-chloro-4-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. [M+H] Calc'd for C₁₆H₁₀ClFN₄O, 329.Found, 329.

B.2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.28 (2H, s), 6.02 (1H, d, J=2.0 Hz),7.42-7.52 (2H, m), 7.61 (1H, d, J=1.6 Hz), 7.74-7.78 (2H, m), 8.08 (1H,s), 8.68 (1H, d, J=5.2 Hz), 13.90 (1H, s). [M+H] Calc'd forC₁₆H₁₁ClFN₃O₃, 348. Found, 348.

Example 772-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid A.2-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-cyclopropylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 0.61-0.65(2H, m), 0.89-0.94 (2H, m), 1.91-1.84 (1H, m), 5.12 (2H, s), 5.67 (1H,d, J=1.6 Hz), 7.01-7.24 (4H, m), 7.32-7.33 (1H, m), 7.50 (1H, d, J=1.2Hz), 7.95 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₉H₁₆N₄O,317. Found, 317.

B. 2-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid

The title compound was prepared from2-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.64-0.67 (2H, m), 0.91-1.96 (2H, m),1.87-1.93 (1H, m), 5.21 (2H, s), 6.00 (1H, d, J=1.6 Hz), 7.06-7.08 (2H,m), 7.33-7.35 (2H, m), 7.58 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=1.2 Hz,J=5.2 Hz), 8.06 (1H, s), 8.67 (1H, d, J=4.8 Hz), 13.91 (1H, s). [M+H]Calc'd for C₁₉H₁₇N₃O₃, 336. Found, 336.

Example 78 Methyl2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 3.90 (3H, s), 5.14 (2H, s), 5.67 (1H, s), 7.09(1H, d, J=8.4 Hz), 7.23 (1H, d, J=9.6 Hz), 7.35 (1H, t, J=8.0 Hz), 7.52(1H, s), 7.72 (1H, d, J=4.4 Hz), 8.26 (1H, s), 8.64 (1H, d, J=3.6 Hz).[M+H] Calc'd for C₁₇H₁₃ClFN₃O₃, 362. Found, 362.

Example 79 Methyl2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 3.90 (3H, s), 5.20 (2H, s), 5.73 (1H, s), 7.07(1H, dd, J=2.0 Hz, J=9.6 Hz), 7.11 (1H, dd, J=2.0 Hz, J=9.6 Hz), 7.43(1H, t, J=8.0 Hz), 7.52 (1H, s), 7.70 (1H, d, J=4.4 Hz), 8.24 (1H, s),8.63 (1H, s). [M+H] Calc'd for C₁₇H₁₃ClFN₃O₃, 362. Found, 362.

Example 80 Methyl2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 3.90 (3H, s), 5.11 (2H, s), 5.68 (1H, s), 7.09(1H, t, J=8.4 Hz), 7.23-7.27 (1H, m), 7.48 (1H, dd, J=1.6 Hz, J=7.2 Hz),7.51 (1H, d, J=1.2 Hz), 7.71 (1H, dd, J=1.6 Hz, J=5.2 Hz), 8.25 (1H, s),8.64 (1H, d, J=4.4 Hz). [M+H] Calc'd for C₁₇H₁₃ClFN₃O₃, 362. Found, 362.

Example 81 Methyl2-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate

The title compound was prepared from2-{5-[(4-cyclopropylbenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylicacid according to the procedure for the preparation of Example 62. ¹HNMR (400 MHz, CDCl₃): δ 0.60-0.64 (2H, m), 0.88-0.93 (2H, m), 1.81-1.85(1H, m), 3.89 (3H, d, J=6.4 Hz), 5.12 (2H, s), 5.67 (1H, s), 7.00-7.26(4H, m), 7.50 (1H, s), 7.68 (1H, d, J=4.8 Hz), 8.26 (1H, s), 8.62 (1H,s). [M+H] Calc'd for C₂₀H₁₉N₃O₃, 350. Found, 350.

Example 822-[5-[1-(4-fluorophenyl)ethoxy]pyrazol-1-yl]pyridine-4-carboxylic acidA. 2-[5-[1-(4-fluorophenyl)ethoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and1-(4-fluorophenyl)ethanol according to the procedure for the preparationof Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.65 (3H, d, J=6.4Hz), 5.24 (1H, q, J=6.4 Hz), 5.44 (1H, d, J=2.0 Hz), 6.95-7.00 (2H, m),7.27-7.30 (2H, m), 7.35 (1H, dd, J=0.8 Hz, J=5.2 Hz), 7.41 (1H, d, J=2.0Hz), 7.97 (1H, s), 8.66 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₃FN₄O,309. Found, 309.

B. 2-[5-[1-(4-fluorophenyl)ethoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[1-(4-fluorophenyl)ethoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆) δ: 1.58 (3H, d, J=6.4 Hz), 5.53 (1H, q, J=6.4Hz), 5.81 (1H, d, J=1.6 Hz), 7.16-7.20 (2H, m), 7.49-7.52 (3H, m), 7.76(1H, dd, J=1.2 Hz, J=5.2 Hz), 8.05 (1H, s), 8.70 (1H, d, J=4.8 Hz),13.97 (1H, s). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.587 min. [M+H] Calc'd for C₁₇H₁₄FN₃O₃, 328.Found, 328.

Example 832-[5-[(3,3-difluorocyclobutyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(3,3-difluorocyclobutyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3,3-difluorocyclobutyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.48-2.71(5H, m), 5.14 (2H, d, J=4.4 Hz), 5.64 (1H, d, J=1.6 Hz), 7.34 (1H, dd,J=0.4 Hz, J=4.8 Hz), 7.51 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.61 (1H, d,J=4.8 Hz). [M+H] Calc'd for C₁₄H₁₂F₂N₄O, 291. Found, 291.

B.2-[5-[(3,3-difluorocyclobutyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3,3-difluorocyclobutyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.50-2.69 (5H, m), 4.23 (2H, d, J=4.4 Hz),5.96 (1H, d, J=2.0 Hz), 7.60 (1H, d, J=1.6 Hz), 7.76 (1H, dd, J=1.2 Hz,J=4.8 Hz), 8.07 (1H, s), 8.66 (1H, d, J=5.2 Hz), 13.87 (1H, s). LCMS(mobile phase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%,Rt=2.273 min. [M+H] Calc'd for C₁₄H₁₃F₂N₃O₃, 310. Found, 310.

Example 842-[5-[(4-fluorophenyl)methoxy]-4-methylpyrazol-1-yl]pyridine-4-carboxylicacid A. ethyl (E)-3-(dimethylamino)-2-methylprop-2-enoate

A solution ofN,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (2.47g, 14.19 mmol), ethyl propionate (2.17 g, 21.27 mmol) and DMF (2 mL) ina sealed tube was heated to 90° C. for 24 h. Then extracted with ethylacetate, collected the organic phase and washed with water, brine anddried with anhydrous sodium sulfate. Organic phase was concentrated andpurified by silica gel chromatograph to give 0.68 g of the titlecompound (30%). ¹H NMR (400 MHz, CDCl₃): δ 1.24 (3H, t, J=7.2 Hz), 1.95(3H, s), 3.00 (6H, s), 4.11 (2H, q, J=7.2 Hz), 7.28 (1H, s). [M+H]Calc'd for C₈H₁₅NO₂, 158. Found, 158.

B. ethyl (E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]-2-methylprop-2-enoate

A solution of ethyl (E)-3-(dimethylamino)-2-methylprop-2-enoate (668 mg,4.25 mmol) and 2-hydrazinylpyridine-4-carbonitrile (570 mg, 4.25 mmol,PREPARATION 2) in 2 mL HOAc and 10 mL EtOH was charged to a flask andthe mixture was heated to 90° C. for 30 min. Cooled to room temperatureand removed the solvent. The residue was dissolved in ethylacetate andwater, aqueous basified with NaHCO₃ sat (pH=8), extracted withethylacetate. The organic phase was washed with brine and dried withanhydrous sodium sulfate and then purified by silica gel chromatographto give 0.65 g of the title compound (62%). [M+H] Calc'd for C₁₂H₁₄N₄O₂,247. Found, 247.

C. 2-(5-hydroxy-4-methylpyrazol-1-yl)pyridine-4-carbonitrile

To a cooled mixture of ethyl(E)-3-[2-(4-cyanopyridin-2-yl)hydrazinyl]-2-methylprop-2-enoate (415 mg,1.69 mmol) in ethanol (18 mL) was added t-BuOK (568 mg, 5.06 mmol)slowly. After that, the mixture was stirred overnight, filtered, thesolid was acidified with HCl (1N), filtered, collected the solid anddried to give 250 mg of the title compound (74%). ¹H NMR (400 MHz,CDCl₃): δ 1.93 (3H, s), 7.55 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.64 (1H, s),8.64 (1H, d, J=4.8 Hz), 8.72 (1H, s). [M+H] Calc'd for C₁₀H₈N₄O, 201.Found, 201.

D.2-[5-[(4-fluorophenyl)methoxy]-4-methylpyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-4-methylpyrazol-1-yl)pyridine-4-carbonitrile and4-fluorobenzyl alcohol according to the procedure for the preparation ofExample 39, part C. ¹H NMR (300 MHz, CDCl₃): δ 1.91 (3H, s), 5.14 (2H,s), 7.26 (2H, s), 7.33-7.37 (3H, m), 7.46 (1H, s), 7.99 (1H, s), 8.62(1H, d, J=5.1 Hz). [M+H] Calc'd for C₁₇H₁₃FN₄O, 309. Found, 309.

E.2-[5-[(4-fluorophenyl)methoxy]-4-methylpyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-fluorophenyl)methoxy]-4-methylpyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.89 (3H, s), 5.16 (2H, s), 7.14-7.19 (2H, m),7.44-7.47 (2H, m), 7.53 (1H, s), 7.75 (1H, dd, J=1.6 Hz, J=4.8 Hz), 8.03(1H, s), 8.69 (1H, d, J=5.2 Hz). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.614 min. [M+H] Calc'dfor C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 852-[4-ethyl-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. ethyl (2E)-2-(dimethylaminomethylidene)butanoate

The title compound was prepared fromN,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine andethyl butanoate according to the procedure for the preparation ofExample 84, part A. [M+H] Calc'd for C₉H₁₇NO₂, 172. Found, 172.

B. ethyl(2E)-2-[[2-(4-cyanopyridin-2-yl)hydrazinyl]methylidene]butanoate

The title compound was prepared from ethyl(2E)-2-(dimethylaminomethylidene)butanoate and2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) according to theprocedure for the preparation of Example 84, part B. [M+H] Calc'd forC₁₃H₁₆N₄O₂, 261. Found, 261.

C. 2-(4-ethyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared from ethyl(2E)-2-[[2-(4-cyanopyridin-2-yl)hydrazinyl]methylidene]butanoateaccording to the procedure for the preparation of Example 84, part C.[M+H] Calc'd for C₁₁H₁₀N₄O, 215. Found, 215.

D.2-[4-ethyl-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(4-ethyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile and4-fluorobenzyl alcohol according to the procedure for the preparation ofExample 39, part C. [M+H] Calc'd for C₁₅H₁₅FN₄O, 323. Found, 323.

E.2-[4-ethyl-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[4-ethyl-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.11 (3H, t, J=7.6 Hz), 2.32 (2H, q, J=7.6Hz), 5.14 (2H, s), 7.15-7.20 (2H, m), 7.44-7.47 (2H, m), 7.61 (1H, s),7.75 (1H, dd, J=1.6 Hz, J=4.8 Hz), 8.04 (1H, s), 8.69 (1H, d, J=5.2 Hz),13.89 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.633 min. [M+H] Calc'd for C₁₈H₁₆FN₃O₃, 342.Found, 342.

Example 862-[5-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2,4-difluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.19 (2H,s), 5.74 (1H, d, J=2.0 Hz), 6.78-6.86 (2H, m), 7.33 (1H, dd, J=1.2 Hz,J=4.8 Hz), 7.39-7.45 (1H, m), 7.51 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.62(1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₆H₁₀F₂N₄O, 313. Found, 313.

B. 2-[5-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2,4-difluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.29 (2H, s), 6.08 (1H, d, J=2.0 Hz),7.11-7.15 (1H, m), 7.27-7.33 (1H, m), 7.61 (1H, d, J=2.0 Hz), 7.68 (1H,dd, J=8.0, 15.6 Hz), 7.72-7.75 (1H, m), 8.04 (1H, s), 8.65 (1H, d, J=5.2Hz). LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.1% TFA): purityis >95%, Rt=3.349 min. [M+H] Calc'd for C₁₆H₁₁F₂N₃O₃, 332. Found, 332.

Example 872-[5-[(3,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(3,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3,4-dichlorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.12 (2H,s), 5.66 (1H, d, J=1.6 Hz), 7.20 (1H, d, J=2.0 Hz), 7.35 (1H, dd, J=1.2,5.2 Hz), 7.40 (1H, d, J=8.0 Hz), 7.52 (2H, m), 7.98 (1H, s), 8.64 (1H,d, J=4.8 Hz). [M+H] Calc'd for C₁₆H₁₀Cl₂N₄O, 345. Found, 345.

B. 2-[5-[(3,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.30 (2H, s), 6.01 (1H, d, J=2.0 Hz),7.46-7.48 (1H, m), 7.60-7.67 (2H, m), 7.76-7.80 (2H, m), 8.09 (1H, s),8.69 (1H, d, J=5.2 Hz). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.773 min. [M+H] Calc'dfor C₁₆H₁₁Cl₂N₃O₃, 364. Found, 364.

Example 882-[5-[(2,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(2,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2,4-dichlorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.29 (2H,s), 5.79 (1H, d, J=1.6 Hz), 7.29-7.32 (1H, m), 7.42 (1H, dd, J=1.2, 5.2Hz), 7.45 (1H, d, J=2.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=1.6Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₁₆H₁₀Cl₂N₄O, 345. Found, 345.

B. 2-[5-[(2,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2,4-dichlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.33 (2H, s), 6.08 (1H, d, J=2.4 Hz), 7.50(1H, dd, J=2.4, 8.4 Hz), 7.62 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=1.6 Hz),7.72 (1H, d, J=8.4 Hz), 7.76 (1H, dd, J=1.6, 4.8 Hz), 8.09 (1H, s), 8.69(1H, d, J=4.8 Hz), 13.88 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.773 min. [M+H] Calc'dfor C₁₆H₁₁Cl₂N₃O₃, 364. Found, 364.

Example 892-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.36 (3H,s), 5.18 (2H, s), 5.77 (1H, d, J=2.0 Hz), 7.18-7.22 (2H, m), 7.34 (1H,d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.58 (1H, d, J=2.0 Hz),8.00 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₇H₁₃ClN₄O, 325.Found, 325.

B.2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.34 (3H, s), 5.26 (2H, s), 6.09 (1H, d, J=2.0Hz), 7.27 (1H, dd, J=2.4, 8.0 Hz), 7.31 (1H, s), 7.51 (1H, d, J=8.0 Hz),7.61 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=1.6, 4.8 Hz), 8.05 (1H, s), 8.66(1H, d, J=4.8 Hz), 13.92 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.773 min. [M+H] Calc'dfor C₁₇H₁₄ClN₃O₃, 344. Found, 344.

Example 902-[5-[(4-chloro-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(4-chloro-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-methoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 3.89 (3H,s), 5.22 (2H, s), 5.78 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=2.0 Hz),6.95-6.98 (1H, m), 7.33-7.35 (1H, m), 7.39 (1H, dd, J=1.2, 5.2 Hz),7.57-7.58 (1H, m), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₇H₁₃ClN₄O₂, 341. Found, 341.

B.2-[5-[(4-chloro-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.84 (3H, s), 5.22 (2H, s), 6.00 (1H, d, J=2.0Hz), 7.03 (1H, dd, J=2.0, 8.4 Hz), 7.13 (1H, d, J=1.6 Hz), 7.49-7.51(1H, m), 7.58 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=0.8 Hz, J=4.8 Hz), 8.05(1H, s), 8.65 (1H, d, J=5.2 Hz). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.706 min. [M+H]Calc'd for C₁₇H₁₄ClN₃O₄, 360. Found, 360.

Example 912-[5-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-3-(trifluoromethyl)phenyl]methanol according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ5.25 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.6, 5.2 Hz), 7.54(2H, s), 7.58 (1H, d, J=2.0 Hz), 7.89 (1H, s), 8.00 (1H, s), 8.06 (1H,s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₀ClF₃N₄O, 379. Found,379.

B.2-[5-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-3-(trifluoromethyl)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.39 (2H, s), 6.03 (1H, d, J=2.4 Hz), 7.62(1H, d, J=1.6 Hz), 7.75-7.80 (3H, m), 8.05 (1H, s), 8.09 (1H, s), 8.67(1H, d, J=5.2 Hz), 13.93 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.773 min. [M+H] Calc'dfor C₁₇H₁₁ClF₃N₃O₃, 398. Found, 398.

Example 922-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (3-chloro-4-methylphenyl)methanol

To a solution of 4-chloro-2-methylbenzoic acid (800 mg, 4.69 mmol) inTHF (8 mL) that was cooled at 0° C., BH₃.THF (14 mL, 1M in THF) wasadded into the solution drop wise. The mixture was then stirred at r.t.overnight. Add methanol to the system at 0° C. slowly until no gasreleased. Remove the solvent and the residue was extracted withethylacetate, concentrated the organic phase to give 894 mg of the titlecompound (85%). ¹H NMR (400 MHz, CDCl₃): δ 2.36 (3H, s), 4.63 (2H, s),7.13-7.22 (2H, m), 7.35 (1H, s).

B.2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-chloro-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.38 (3H,s), 5.18 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.19-7.25 (2H, m), 7.41 (1H,dd, J=1.2, 4.8 Hz), 7.44 (1H, s), 7.57 (1H, d, J=1.6 Hz), 8.03 (1H, s),8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₇H₁₃ClN₄O, 325. Found, 325.

C.2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.31 (3H, s), 5.23 (2H, s), 5.94 (1H, d, J=2.0Hz), 7.31-7.37 (2H, m), 7.52-7.54 (2H, m), 7.65 (1H, d, J=4.8 Hz), 7.94(1H, s), 8.45 (1H, d, J=4.8 Hz). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.787 min. [M+H]Calc'd for C₁₇H₁₄ClN₃O₃, 344. Found, 344.

Example 932-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-fluoro-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.28 (3H,s), 5.19 (2H, s), 5.72 (1H, d, J=2.0 Hz), 7.18-7.20 (1H, m), 7.07-7.11(2H, m), 7.41 (1H, dd, J=1.2, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H,s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₃FN₄O, 309. Found,309.

B.2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.22 (3H, s), 5.25 (2H, s), 6.00 (1H, d, J=2.0Hz), 7.19-7.31 (3H, m), 7.59 (1H, d, J=1.6 Hz), 7.76-7.77 (1H, m), 8.07(1H, s), 8.68 (1H, d, J=5.2 Hz), 13.91 (1H, s). LCMS (mobile phase:5%-95% Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.337 min. [M+H]Calc'd for C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 942-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2,3-difluoro-4-methylphenyl)methanol

The title compound was prepared from 2,3-difluoro-4-methyl-benzoic acidaccording to the procedure for the preparation of Example 92, part A. ¹HNMR (400 MHz, CDCl₃): δ 2.36 (3H, s), 4.63 (2H, s), 7.13-7.22 (2H, m),7.35 (1H, s).

B.2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2,3-difluoro-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.32 (3H,s), 5.28 (2H, s), 5.80 (1H, s), 6.98 (1H, d, J=6.8 Hz), 7.11 (1H, d,J=7.2 Hz), 7.40 (1H, d, J=5.2 Hz), 7.58 (1H, s), 8.01 (1H, s), 8.70 (1H,d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₂F₂N₄O, 327. Found, 327.

C.2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.27 (3H, s), 5.32 (2H, s), 6.08 (1H, s),7.10-7.14 (1H, m), 7.28-7.31 (1H, m), 7.61 (1H, s), 7.75 (1H, d, J=4.8Hz), 8.03 (1H, s), 8.66 (1H, d, J=4.8 Hz), 13.90 (1H, s). LCMS (mobilephase: 5%-95% Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.269min. [M+H] Calc'd for C₁₇H₁₃F₂N₃O₃, 346. Found, 346.

Preparation 5 methyl 3-amino-4-ethylbenzoate A. 4-ethyl-3-nitrobenzoicacid

To a suspension of 4-ethyl benzoic acid (4.53 g, 30.16 mmol) inconcentrated sulfuric acid (24 mL) at 0° C. was added nitric acid (12mL). The mixture was stirred for 1.5 h at 0° C. Poured into ice water,filtered and dried the solid to give 5.79 g of the title compound (98%).¹H NMR (400 MHz, DMSO-d₆): δ 1.23 (3H, t, J=7.2 Hz), 2.88 (2H, q, J=7.2Hz), 7.67 (1H, d, J=8.0 Hz), 8.15 (1H, dd, J=1.6, 8.0 Hz), 8.36 (1H, d,J=1.6 Hz).

B. methyl 4-ethyl-3-nitrobenzoate

To a suspension of 4-ethyl-3-nitrobenzoic acid (5.76 g, 29.53 mmol) inmethanol (30 mL) at 0° C., was added SOCl₂ (10.54 g, 88.61 mmol) slowly,stirred at this temperature for 1 h, then heated to 50° C. and stirredat this temperature for 3 h. Cooled to room temperature and removed thesolvent, the residue was extracted with ethyl acetate, and concentratedto give 6.05 g of the title compound (98%). ¹H NMR (400 MHz, CDCl₃): δ1.31 (3H, t, J=7.2 Hz), 2.97 (2H, q, J=7.2 Hz), 3.96 (3H, s), 7.47 (1H,d, J=8.4 Hz), 8.17 (1H, dd, J=1.6, 8.4 Hz), 8.52 (1H, d, J=1.6 Hz).

C. methyl 3-amino-4-ethylbenzoate

Charged methyl 4-ethyl-3-nitrobenzoate (5.0 g, 23.92 mmol), Pd/C (500mg) and methanol (50 mL) to a flask, purged with hydrogen and stirred atr.t. overnight. It was then filtered and concentrated to give 4.0 g ofthe title compound (94%). ¹H NMR (400 MHz, CDCl₃): δ 1.26 (3H, t, J=7.6Hz), 2.54 (2H, q, J=7.6 Hz), 3.73 (2H, s), 3.87 (3H, s), 7.12 (1H, d,J=8.0 Hz), 7.35 (1H, s), 7.41 (1H, d, J=7.6 Hz). [M+H] Calc'd forC₁₀H₁₃NO₂, 180. Found, 180.

Example 952-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 3-chloro-4-ethylbenzoate

Charge NaNO₂ (579 mg, 8.37 mmol) and concentrated sulfuric acid (6 mL)to a flask. As methyl 3-amino-4-ethylbenzoate (1.37 g, 7.62 mmol,PREPARATION 5) in acetic acid (18 mL) was added at 0° C., color of themixture turned to yellow, and then stirred at 5° C. for 1.5 h. Thesolution above was added to a dark mixture of CuCl (1.65 g, 16.65 mmol)in concentrated HCl (18 mL) slowly at 0° C., stirred for 2 h, and pouredinto ice water, extracted with DCM, the organic phase was concentratedto give 582 mg of the title compound (38%). ¹H NMR (400 MHz, CDCl₃): δ1.25 (3H, t, J=8.0 Hz), 2.80 (2H, q, J=7.6 Hz), 3.91 (3H, s), 7.30 (1H,d, J=7.6 Hz), 7.85 (1H, dd, J=1.2, 7.6 Hz), 8.01 (1H, d, J=1.6 Hz).

B. (3-chloro-4-ethylphenyl)methanol

To a solution of methyl 3-chloro-4-ethylbenzoate (367 mg, 1.85 mmol) inTHF (5 mL) that cooled to −50° C., LiAlH₄ (141 mg, 2.70 mmol) was addedin portions. After which, the mixture was stirred at this temperaturefor 1 h. Added water (0.2 mL) slowly, followed by NaOH (aq, 10%, 0.2 mL)and water (0.6 mL), the resulted mixture was filtered and washed withTHF, concentrated the filtrate to give 308 mg of the title compound(98%). ¹H NMR (400 MHz, CDCl₃): δ 1.22 (3H, t, J=7.6 Hz), 2.74 (2H, q,J=7.6 Hz), 4.63 (2H, d, J=5.2 Hz), 7.17-7.23 (2H, m), 7.35 (1H, s).

C.2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-chloro-4-ethylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H,t, J=8.0 Hz), 2.76 (2H, t, J=8.0 Hz), 5.18 (2H, s), 5.74 (1H, d, J=0.8Hz), 7.26 (2H, s), 7.40-7.44 (2H, m), 7.57 (1H, s), 8.03 (1H, s), 8.72(1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₅ClN₄O, 339. Found, 339.

C.2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.15 (3H, t, J=10.0 Hz), 2.68 (2H, q, J=10.0Hz), 5.23 (2H, s), 5.95 (1H, d, J=2.4 Hz), 7.36 (2H, s), 7.53 (2H, d,J=2.8 Hz), 7.67 (1H, d, J=6.4 Hz), 7.96 (1H, s), 8.47 (1H, d, J=6.4 Hz).LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.1% TFA): purity is >95%,Rt=3.773 min. [M+H] Calc'd for C₁₈H₁₆ClN₃O₃, 358. Found, 358.

Example 962-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-ethyl-3-fluorobenzoate

At 0° C., NaNO₂ (667 mg, 9.66 mmol) was added to a solution of methyl3-amino-4-ethylbenzoate (1.57 g, 8.78 mmol, PREPARATION 5) in Py-HF (20mL) in portions. The mixture was then heated to 25° C. for 5 h, pourinto ice water, and extracted with DCM, concentrated the organic phasefor silica gel chromatograph (PE/EA=10/1) to give 650 mg of the titlecompound (40%). ¹H NMR (400 MHz, CDCl₃): δ 1.24 (3H, t, J=7.6 Hz), 2.72(2H, q, J=7.6 Hz), 3.91 (3H, s), 7.25-7.29 (1H, m), 7.65 (1H, dd, J=1.2,10.4 Hz), 7.75 (1H, dd, J=1.6, 8.0 Hz).

B. (4-ethyl-3-fluorophenyl)methanol

The title compound was prepared from methyl 4-ethyl-3-fluorobenzoateaccording to the procedure for the preparation of Example 95, part B. ¹HNMR (400 MHz, CDCl₃): δ 1.22 (3H, t, J=8.0 Hz), 2.66 (2H, q, J=8.0 Hz),4.64 (2H, s), 7.01-7.05 (2H, m), 7.18 (1H, t, J=8.0 Hz).

C.2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-ethyl-3-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.16 (3H,t, J=7.6 Hz), 2.60 (2H, t, J=7.6 Hz), 5.13 (2H, s), 5.66 (1H, d, J=1.2Hz), 7.02-7.05 (2H, m), 7.14-7.18 (1H, m), 7.34 (1H, d, J=5.2 Hz), 7.50(1H, d, J=1.2 Hz), 7.96 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₈H₁₅FN₄O, 323. Found, 323.

D.2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.15 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6Hz), 5.26 (2H, s), 6.01 (1H, d, J=1.6 Hz), 7.20-7.33 (3H, m), 7.60 (1H,d, J=1.6 Hz), 7.76 (1H, dd, J=1.2, 4.8 Hz), 8.08 (1H, s), 8.69 (1H, d,J=4.8 Hz)

LCMS (mobile phase: 5%-95% Acetonitrile-Water-0.1% TFA): purity is >95%,Rt=3.634 min. [M+H] Calc'd for C₁₅H₁₆FN₃O₃, 342. Found, 342.

Preparation 6 methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate

A solution of methyl2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate (765mg, 1.97 mmol, EXAMPLE 68) in DCM (8 mL) was purged with nitrogen andcooled to −78° C. BBr₃ (6 mL, 5.93 mmol, 1M in DCM) was added at thistemperature. Thereto, the mixture was stirred at the same temperaturefor an hour, methanol was added until no gas released, and then theabove mixture was basified with NaHCO₃ aq (pH=3). Extracted withethylacetate three times, and the organic phase was washed with brineand dried with Na₂SO₄, concentrated and the residue was washed withethylacetate to give 260 mg of the title compound (60%). ¹H NMR (400MHz, CD₃OD): δ 4.02 (3H, s), 7.91-7.97 (2H, m), 8.69-8.70 (2H, m). [M+H]Calc'd for C₁₀H₉N₃O₃, 220. Found, 220.

Example 972-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid A.methyl 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from methyl2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and(3-cyanophenyl)methanol according to the procedure for the preparationof Example 39, part C. [M+H] Calc'd for C₁₈H₁₄N₄O₃, 335. Found, 335.

B. 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

A solution of methyl2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (1.0eq) and LiOH.H₂O (3.0 eq) in a mixture of water (2 mL) and THF (2 mL)was stirred at room temperature for 30 min. Diluted with another 2 mLwater, and the mixture was washed with ethyl acetate twice (6 mL×2). Thewater phase was acidified with 1N HCl (pH=3), filtered and dried thesolid to give the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 5.36 (2H,s), 6.03 (1H, s), 7.61-7.64 (2H, m), 7.77-7.78 (1H, m), 7.82-7.84 (2H,m), 7.96 (1H, s), 8.09 (1H, s), 8.69 (1H, d, J=4.4 Hz), 13.92 (1H, s).LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=2.106 min. [M+H] Calc'd for C₁₇H₁₂N₄O₃, 321. Found, 321.

Example 98 methyl2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from methyl2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and(4-cyanophenyl)methanol according to the procedure for the preparationof Example 39, part C. [M+H] Calc'd for C₁₈H₁₄N₄O₃, 335. Found, 335.

Example 992-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared from methyl2-[5-[(4-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate(EXAMPLE 98) according to the procedure for the preparation of Example97, part B. ¹H NMR (400 MHz, DMSO-d₆): δ 5.41 (2H, s), 6.00 (1H, d,J=2.0 Hz), 7.61 (1H, d, J=1.6 Hz), 7.67-7.69 (2H, m), 7.77 (1H, dd,J=0.8 Hz, J=4.8 Hz), 7.87-7.89 (2H, m), 8.10 (1H, s), 8.70 (1H, d, J=5.2Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02%NH₄Ac): purity is >95%, Rt=2.104 min. [M+H] Calc'd for C₁₇H₁₂N₄O₃, 321.Found, 321.

Example 100 methyl2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid (EXAMPLE 92) according to the procedure for the preparation ofExample 62. ¹H NMR (400 MHz, CDCl₃): δ 2.38 (3H, s), 3.96 (3H, s), 5.18(2H, s), 5.74 (1H, d, J=1.6 Hz), 7.21-7.26 (2H, m), 7.45 (1H, s), 7.58(1H, d, J=2.0 Hz), 7.77-7.78 (1H, m), 8.33 (1H, s), 8.71 (1H, d, J=5.2Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.628 min. [M+H] Calc'd for C₁₆H₁₆ClN₃O₃, 358. Found, 358.

Example 101 methyl2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid (EXAMPLE 93) according to the procedure for the preparation ofExample 62. ¹H NMR (400 MHz, CDCl₃): δ 2.28 (3H, s), 3.97 (3H, s), 5.21(2H, s), 5.75 (1H, s), 7.09-7.21 (3H, m), 7.60 (1H, s), 7.79 (1H, d,J=4.8 Hz), 8.35 (1H, s), 8.73 (1H, s). LCMS (mobile phase: 20%-95%Acetonitrile-Water-0.1% NH₄OH): purity is >95%, Rt=3.936 min. [M+H]Calc'd for C₁₈H₁₆FN₃O₃, 342. Found, 342.

Example 102 methyl2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid (EXAMPLE 95) according to the procedure for the preparation ofExample 62. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H, t, J=7.6 Hz), 2.76 (2H,q, J=7.6 Hz), 3.97 (3H, s), 5.18 (2H, s), 5.75 (1H, s), 7.26 (2H, s),7.45 (1H, s), 7.58 (1H,$), 7.78 (1H, d, J=8.0 Hz), 8.33 (1H, s), 8.72(1H, d, J=0.8 Hz). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.02%NH₄OH): purity is >95%, Rt=4.602 min. [M+H] Calc'd for C₁₉H₁₈ClN₃O₃,372. Found, 372.

Example 103 methyl2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from2-[5-[(2,3-difluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid (EXAMPLE 94) according to the procedure for the preparation ofExample 62. ¹H NMR (400 MHz, CDCl₃): δ 2.31 (3H, s), 3.96 (3H, s), 5.27(2H, s), 5.80 (1H, d, J=6.4 Hz), 6.94-6.97 (1H, m), 7.13-7.17 (1H, m),7.58 (1H, s), 7.76 (1H, d, J=4.0 Hz), 8.30 (1H, s), 8.69 (1H, d, J=2.4Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH₄Ac): purityis >95%, Rt=3.485 min. [M+H] Calc'd for C₁₈H₁₅F₂N₃O₃, 360. Found, 360.

Example 104 methyl2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from2-[5-[(4-ethyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid (EXAMPLE 96) according to the procedure for the preparation ofExample 62. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H, t, J=7.6 Hz), 2.67 (2H,q, J=7.6 Hz), 3.97 (3H, s), 5.20 (2H, s), 5.75 (1H, d, J=1.6 Hz),7.12-7.23 (3H, m), 7.58 (1H, d, J=2.0 Hz), 7.78 (1H, dd, J=1.6, 5.2 Hz),8.34 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=3.783 min. [M+H]Calc'd for C₁₉H₁₈FN₃O₃, 356. Found, 356.

Preparation 7 5-chloro-2-(hydroxymethyl)phenol

BH₃ (1M in THF, 359 mL) was added into a solution of4-chloro-2-hydroxybenzoic acid (20.63 g, 0.12 mmol) in THF (40 mL) dropwise at 0° C. After which, the mixture was stirred at r.t. overnight.Extracted with EA twice, and washed the organic phase with brine anddried with anhydrous Na₂SO₄, concentrated to give the title compound (12g, 63%). ¹H NMR (400 MHz, DMSO-d₆): δ 4.42 (2H, s), 4.97-5.06 (1H, m),6.77 (1H, d, J=2.0 Hz), 6.82 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.27 (1H, d,J=8.4 Hz), 9.85 (1H, s).

Example 1052-[5-[(4-chloro-2-phenylmethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-chloro-2-phenylmethoxyphenyl)methanol

(Bromomethyl)benzene (323 mg, 1.89 mmol) was added to a mixture of5-chloro-2-(hydroxymethyl)phenol (300 mg, 1.89 mmol, PREPARATION 7) andNaOH (1.1 mL, 2M in water) in ethanol (5 mL) at r.t. slowly. Thereaction mixture was stirred overnight. Poured into ice water, andextracted with ethyl acetate twice, and washed the organic phase withwater twice, brine and dried with anhydrous Na₂SO₄. The solvents wereremoved and the residue purified by silica gel chromatograph to give 120mg of the title compound (28%).

B.2-[5-[(4-chloro-2-phenylmethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-phenylmethoxyphenyl)methanol according to the procedure forthe preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 5.11(2H, s), 5.27 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.98-7.00 (2H, m),7.33-7.39 (7H, m), 7.55 (1H, d, J=2.0 Hz), 7.99 (1H, s), 8.67 (1H, d,J=5.2 Hz). [M+H] Calc'd for C₂₃H₁₇ClN₄O₂, 417. Found, 417.

C.2-[5-[(4-chloro-2-phenylmethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-phenylmethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.21 (2H, s) 5.22 (2H, s), 5.92 (1H, d, J=1.6Hz), 7.03 (1H, dd, J=1.6 Hz, J=8.0 Hz), 7.19 (1H, d, J=1.2 Hz),7.28-7.39 (5H, m), 7.50-7.52 (2H, m), 7.65 (1H, d, J=4.8 Hz), 7.95 (1H,s), 8.44 (1H, d, J=4.8 Hz). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=4.032 min. [M+H] Calc'dfor C₂₃H₁₈ClN₃O₄, 436. Found, 436.

Example 1062-[5-[[4-chloro-2-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-(cyclopropylmethoxy)phenyl]methanol

Charged 5-chloro-2-(hydroxymethyl)phenol (616 mg, 3.88 mmol, PREPARATION7), bromocyclopropylmethanol (525 mg, 3.88 mmol), K₂CO₃ (1.07 g, 7.77mmol) and DMF (6 mL) to a flask, purged with nitrogen and heated to 80°C. overnight. Poured into ice water, and extracted with ethyl acetatetwice, and washed the organic phase with water twice, brine and driedwith anhydrous Na₂SO₄, removed the solvent for silica gel chromatographto give 108 mg of the title compound (13%). ¹H NMR (400 MHz, CDCl₃): δ0.33-0.37 (2H, m), 0.63-0.68 (2H, m), 1.26-1.28 (1H, m), 3.84 (2H, d,J=7.2 Hz), 4.67 (2H, s), 4.86 (1H, s), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H,dd, J=2.0 Hz, 8.0 Hz), 7.19 (1H, d, J=7.6 Hz).

B.2-[5-[[4-chloro-2-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-(cyclopropylmethoxy)phenyl]methanol according to theprocedure for the preparation of Example 39, part C. [M+H] Calc'd forC₂₀H₁₇ClN₄O₂, 381. Found, 381.

C.2-[5-[[4-chloro-2-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.28-0.29 (2H, m), 0.50-0.54 (2H, m),1.15-1.19 (1H, m), 3.87 (2H, d, J=6.8 Hz), 5.28 (2H, s), 6.99 (1H, d,J=6.4 Hz), 6.92-6.98 (2H, m), 7.41 (1H, d, J=8.0 Hz), 7.60 (1H,$), 7.82(1H, d, J=2.8 Hz), 8.26 (1H, s), 8.63 (1H, d, J=3.2). LCMS (mobilephase: 10%-95% Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.611min. [M+H] Calc'd for C₂₀H₁₈ClN₃O₄, 400. Found, 400.

Example 1072-[5-[(4-chloro-2-propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-chloro-2-propoxyphenyl)methanol

Charge 5-chloro-2-(hydroxymethyl)phenol (997 mg, 6.29 mmol, PREPARATION7), iodopropane (1.17 g, 6.92 mmol), K₂CO₃ (1.74 g, 12.58 mmol) and DMF(6 mL) to a sealed tube. The reaction mixture was heated to 100° C.overnight. It was then poured into ice-water and extracted with ethylacetate twice, washed the organic phase with water twice, brine anddried with Na₂SO₄, concentrated and purified by silica gel chromatographto give the title compound (729 mg, 58%). ¹H NMR (400 MHz, CDCl₃): δ1.05 (3H, t, J=7.2 Hz), 1.79-1.88 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.64(2H, s), 6.85 (1H, d, J=1.2 Hz), 6.91 (1H, dd, J=1.6 Hz, 8.4 Hz), 7.20(1H, d, J=8.0 Hz).

B.2-[5-[(4-chloro-2-propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-propoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.01 (3H,t, J=7.2 Hz), 1.77-1.86 (2H, m), 3.98 (2H, t, J=2.4 Hz), 5.24 (2H, s),5.78 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=1.6 Hz), 6.95 (1H, dd, J=2.0 Hz,8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.58(1H, d, J=1.6 Hz), 8.05 (1H, d, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₉H₁₇ClN₄O₂, 369. Found, 369.

C.2-[5-[(4-chloro-2-propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-propoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.88 (3H, t, J=7.2 Hz), 1.61-1.70 (2H, m),3.98 (2H, t, J=6.4 Hz), 5.20 (2H, s), 6.01 (1H, d, J=2.0 Hz), 7.01 (1H,dd, J=2.0 Hz, 8.4 Hz), 7.10 (1H, d, J=1.6 Hz), 7.49 (1H, d, J=8.4 Hz),7.59 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=0.8 Hz, 5.2 Hz), 8.04 (1H, s),8.66 (1H, d, J=4.8 Hz), 13.86 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.889 min. [M+H]Calc'd for C₁₉H₁₈ClN₃O₄, 388. Found, 388.

Example 1082-[5-[[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 2,2,2-trifluoroethyl 4-methylbenzenesulfonate

To a solution of 4-methylbenzenesulfonyl chloride (3.4 g, 17.83 mmol)and Et₃N (3.61 g, 35.66 mmol) in DCM (80 mL) was added2,2,2-trifluoroethan-1-ol (2.32 g, 23.18 mmol) slowly, the mixture wasthen stirred at r.t. until TLC showed no starting material. Water wasadded to the reaction mixture, and extracted with DCM, collected theorganic phase and washed with brine, dried with anhydrous Na₂SO₄,removed the solvent to give 4.2 g of the title compound (93%). ¹H NMR(400 MHz, CDCl₃): δ 2.47 (3H, s), 4.34 (2H, q, J=8.0 Hz), 7.38 (2H, d,J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz).

B. [4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methanol

Charged 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.62 g, 6.37mmol), 5-chloro-2-(hydroxymethyl)phenol (1.01 g, 6.37 mmol, PREPARATION7), K₂CO₃ (1.76 g, 12.74 mmol) and DMF (7 mL) to a flask; heated to 100°C. overnight. The reaction mixture was then poured into ice-water andextracted with EA twice, washed the organic phase with water twice,brine and dried with Na₂SO₄, concentrated for gel chromatograph to givethe title compound (200 mg, 13%). ¹H NMR (400 MHz, CDCl₃): δ 4.39 (2H,q, J=8.0 Hz), 4.70 (2H, d, J=5.2 Hz), 6.83 (1H, d, J=1.6 Hz), 7.05 (1H,dd, J=1.6 Hz, 8.0 Hz), 7.33 (1H, d, J=7.6 Hz).

C.2-[5-[[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 81% yield from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 4.43 (2H, q, J=8.0 Hz), 5.26 (2H, s), 5.79 (1H, d, J=1.6 Hz),6.91 (1H, d, J=1.6 Hz), 7.10 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.40 (1H, dd,J=1.2 Hz, 5.2 Hz), 7.44 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.04(1H, s), 8.69 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₂ClF₃N₄O₂, 409.Found, 409.

D.2-[5-[[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. 1HNMR (400 MHz, DMSO-d₆): δ 4.87 (2H, q, J=8.0 H), 5.22 (2H, s), 5.99 (1H,d, J=1.6 Hz), 7.16 (1H, dd, J=1.6 Hz, J=8.0 Hz), 7.34 (1H, d, J=1.2 Hz),7.56-7.60 (2H, m), 7.74 (1H, dd, J=0.4 Hz, J=4.8 Hz), 8.05 (1H, s), 8.66(1H, d, J=5.2 Hz), 13.88 (1H, s). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.1% TFA): purity is >95%, Rt=3.505 min. [M+H] Calc'dfor C₁₈H₁₃ClF₃N₃O₄, 428. Found, 428.

Preparation 82-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileA. 4-hydroxybutanoyloxylithium

Charge oxolan-2-one (9.64 g, 0.11 mmol), lithium hydroxide (4.7 g, 0.11mmol), methanol (10 mL) and water (4 mL) to a flask. The reactionmixture was stirred at r.t. for 16 h. The solvent was removed to givethe title compound (14.1 g, 100%) which was used for the next stepwithout further purification.

B. 4-[tert-butyl(dimethyl)silyl]oxybutanoyloxylithium

To a suspension of 4-hydroxybutanoyloxylithium (5.17 g, 41.03 mmol) and1H-imidazole (4.19 g, 61.55 mmol) in DMF (20 mL) was added TBSCl (7.42g, 49.04 mmol) in portions at r.t. The reaction mixture was then stirredovernight. The reaction solution was poured into water and extractedwith ethyl acetate three times. The organic phase separated and washedwith water twice, brine and dried with anhydrous Na₂SO₄. It was thenconcentrated to give the title compound as colorless oil (8.0 g, 89%).[M+H] Calc'd for C₁₀H₂₁LiO₃Si, 225. Found, 225.

C. 4-[tert-butyl(dimethyl)silyl]oxybutanoic acid

To a solution of 4-[tert-butyl(dimethyl)silyl]oxybutanoyloxylithium (8.0g, 35.71 mmol) in ethyl acetate (10 mL), was carefully added KHSO₄ (5%)to adjust pH to about 1. It was then extracted with ethyl acetate threetimes and organic extracts washed with brine and dried with anhydrousNaSO₄. The organic extracts were concentrated to give the title compound(7.4 g, 95%). [M+H] Calc'd for C₁₀H₂₂O₃Si, 219. Found, 219.

D. methyl 4-[tert-butyl(dimethyl)silyl]oxybutanoate

CH₂N₂ (1.04 g, 248.1 mmol) in ether (10 mL) was added to4-[tert-butyl(dimethyl)silyl]oxybutanoic acid (5.41 g, 24.81 mmol) in aflask. The mixture was stirred overnight, concentrated to give the titlecompound (5.44 g, 95%). ¹H NMR (400 MHz, CDCl₃): δ 0.03 (6H, s), 0.88(9H, s), 1.81-184 (2H, m), 2.39 (2H, t, J=7.2 Hz), 3.63 (2H, d, J=6.4Hz), 3.66 (3H, s). [M+H] Calc'd for C₁₁H₂₄O₃Si, 233. Found, 233.

E. methyl(2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-(dimethylaminomethylidene)butanoate

A mixture of methyl 4-[tert-butyl(dimethyl)silyl]oxybutanoate (6.8 g,29.31 mmol) andN,N,N′,N′-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine (5.1 g,29.31 mmol) in DMF (14 mL) in sealed tube was heated to 100° C.overnight. Added water to the mixture at 0° C. and extracted with ethylacetate twice. The organic phase was separated and washed with water(2×) and brine and dried with anhydrous Na₂SO₄. The organic phase wasconcentrated to give the title compound (7.33 g, 91%). [M+H] Calc'd forC₁₄H₂₉NO₃Si, 288. Found, 288.

F. methyl(2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(4-cyanopyridin-2-yl)hydrazinyl]methylidene]butanoate

Charged methyl(2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-(dimethylaminomethylidene)butanoate(7.33 g, 50%, 12.72 mmol), 2-hydrazinopyridine-4-carbonaitrile (1.70 g,12.72 mmol), acetic acid (10 mL) and ethanol (50 mL) to a flask, themixture was heated to 90° C. for 30 min, cooled to r.t. and basifiedwith NaHCO₃ at 0° C. to pH=8. It was then extracted with ethyl acetatetwice, concentrated and purified by silica gel chromatograph(PE/EA=10/1) to give the title compound (3.3 g, 34%). ¹H NMR (400 MHz,CDCl₃): δ 0.04 (6H, d, J=1.6 Hz), 0.89 (9H, s), 1.96-2.17 (2H, m), 3.59(1H, q, J=6.4 Hz), 3.69 (2H, d, J=6.0 Hz), 3.74 (3H, s), 6.91-6.92 (1H,m), 7.19 (1H, d, J=6.0 Hz), 7.38 (1H, s), 8.22 (1H, d, J=5.2 Hz), 8.33(1H, s). [M+H] Calc'd for C₁₈H₂₈N₄O₃Si, 377. Found, 377.

G.2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

To a mixture of methyl(2E)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[2-(4-cyanopyridin-2-yl)hydrazinyl]methylidene]butanoate(3.3 g, 8.77 mmol) in ethanol (50 mL) at 0° C. was added t-BuOK (2.95 g,26.33 mmol). The reaction mixture was stirred overnight at r.t. It wasthen cooled to 0° C., diluted with ethyl acetate, and acidified withNaHSO₄ (5%) to pH=3. The organic phase was separated and concentrated toa residue which was washed with PE/EA to give 300 mg of the titlecompound (10%). ¹H NMR (400 MHz, CD₃OD): δ 0.00 (6H, s), 0.85 (9H, s),2.49 (2H, d, J=6.4 Hz), 3.74 (2H, d, J=6.4 Hz), 7.48 (1H, dd, J=1.2 Hz,4.8 Hz), 7.60 (1H, s), 8.57 (1H, d, J=4.8 Hz), 8.61-8.63 (1H, m). [M+H]Calc'd for C₁₇H₂₄N₄O₂Si, 345. Found, 345.

H.2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 43% yield from2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileand (4-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 0.00 (6H,s), 0.85 (9H, s), 2.50 (2H, t, J=6.4 Hz), 3.68 (2H, d, J=6.4 Hz), 5.12(2H, s), 6.98-7.02 (2H, m), 7.30-7.34 (3H, m), 7.54 (1H, s), 7.98 (1H,s), 8.58 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₂₄H₂₉FN₄O₂Si, 453. Found,453.

Example 1092-[5-[(4-fluorophenyl)methoxy]-4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 50% yield from2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile(PREPARATION 8) according to the procedure for the preparation ofExample 28, part E. ¹H NMR (400 MHz, DMSO-d₆): δ 2.47 (2H, t, J=6.4 Hz),3.52-3.57 (2H, m), 4.73 (1H, t, J=4.8 Hz), 5.16 (2H, s), 7.17 (2H, t,J=8.8 Hz), 7.46 (2H, dd, J=6.4 Hz, 8.4 Hz), 7.61 (1H, s), 7.75 (1H, dd,J=1.6 Hz, 4.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=5.2 Hz). LCMS (mobilephase: 5%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.154min. [M+H] Calc'd for C₁₈H₁₆FN₃O₄, 358. Found, 358.

Example 1102-[4-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(4-fluorophenyl)methoxy]-4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile

To a mixture of2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile(60 mg, 0.13 mmol, PREPARATION 8) in THF (5 mL) was added 3N HCl (1 mL)at 0° C. The reaction mixture was stirred for 2 h at r.t. Cooled to 0°C., added ethyl acetate, water and acidified with NaHCO₃ to pH=8, andthe mixture was then extracted with ethyl acetate and concentrated toafford the title compound (40 mg, 91%). [M+H] Calc'd for C₁₈H₁₅FN₄O₂,339. Found, 339.

B.2-[1-(4-cyanopyridin-2-yl)-5-[(4-fluorophenyl)methoxy]pyrazol-4-yl]ethylmethanesulfonate

To a mixture of2-[5-[(4-fluorophenyl)methoxy]-4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile(40 mg, 0.12 mmol), Et₃N (26 mg, 0.26 mmol) in DCM (5 mL) was addedMeSO₂Cl (17 mg, 0.15 mmoL) at 0° C. The reaction mixture was thenstirred for 2 h at r.t. Water was added and extracted with DCM andconcentrated to afford the title compound (42 mg, 87%). [M+H] Calc'd forC₁₉H₁₇FN₄O₄S, 417. Found, 417.

C.2-[4-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of2-[1-(4-cyanopyridin-2-yl)-5-[(4-fluorophenyl)methoxy]pyrazol-4-yl]ethylmethanesulfonate (42 mg, 0.1 mmol) and dimethylamine hydrochloride (41mg, 0.5 mmol) in ACN (3 mL) was added K₂CO₃ (276 mg, 2 mmol) and KI (62mg, 0.4 mmol) at rt. The reaction mixture was heated to 80° C. andstirred overnight. Filtered, solvent removed and purified by prep-HPLCto give the title compound (16 mg, 44%). ¹H NMR (400 MHz, CDCl₃): δ 2.45(6H, s), 2.56-2.61 (2H, m), 2.69-2.73 (2H, m), 5.16 (2H, s), 7.03-7.07(2H, m), 7.35-7.41 (3H, m), 7.53 (1H, s), 8.03 (1H, s), 8.64 (1H, d,J=4.8 Hz). [M+H] Calc'd for C₂₀H₂₀FN₅O, 366. Found, 366.

D.2-[4-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

A mixture of2-[4-[2-(dimethylamino)ethyl]-5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile(16 mg, 0.04 mmol) in NaOH aqueous (5M, 0.1 mL) and ethanol (2 mL) washeated to reflux for half an hour. It was then cooled in an ice-waterbath, adjusted pH to 3˜4, filtered, collected the solid and dried togive the title compound (11 mg, 50%). ¹H NMR (400 MHz, CD₃OD): δ2.68-2.71 (2H, m), 2.81 (6H, s), 3.21-3.24 (2H, m), 5.08 (2H, s),6.91-6.96 (2H, m), 7.24-7.27 (2H, m), 7.56 (1H, s), 7.77 (1H, d, J=4.4Hz), 8.04 (1H, s), 8.56 (1H, br). LCMS (mobile phase: 5%-95%Acetonitrile-Water-0.02% NH₄Ac): purity is >95%, Rt=2.153 min. [M+H]Calc'd for C₂₀H₂₁FN₄O₃, 385. Found, 385.

Example 1112-[5-[(2-butoxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-chloro-2-butoxyphenyl)methanol

Charged 5-chloro-2-(hydroxymethyl)phenol (965 mg, 6.09 mmol, PREPARATION7), bromobutane (918 mmol, 6.70 mmol), K₂CO₃ (1.68 g, 12.19 mmol) andDMF (6 mL) to a sealed tube, and the mixture was heated to 100° C.overnight. After cooling to room temperature, the reaction mixture waspoured into ice water, extracted with ethyl acetate twice, and theorganic extract was washed with water, brine and dried with anhydrousNa₂SO₄. Solvent removed and the residue was purified by flash columnchromatograph to give 600 mg of the title compound (46%). ¹H NMR (300MHz, CDCl₃): δ 0.98 (3H, t, J=7.2 Hz), 1.46-1.56 (2H, m), 1.75-1.84 (2H,m), 2.23 (1H, t, J=6.0 Hz), 4.00 (2H, t, J=6.3 Hz), 4.64 (2H, d, J=6.3Hz), 6.85 (1H, d, J=1.8 Hz), 6.91 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.19 (1H,d, J=7.8 Hz).

B.2-[5-[(2-butoxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-butoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 0.95 (3H,t, J=7.2 Hz), 1.41-1.48 (2H, m), 1.74-1.79 (2H, m), 4.01 (2H, t, J=6.4Hz), 5.23 (2H, s), 5.77 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=2.0 Hz), 6.95(1H, dd, J=1.6 Hz, 7.6 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8Hz). [M+H] Calc'd for C₂₀H₁₉ClN₄O₂, 383. Found, 383.

C.2-[5-[(2-butoxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-butoxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d6): δ 0.82 (3H, t, J=7.2 Hz), 1.27-1.36 (2H, m),1.57-1.64 (2H, m), 4.00 (2H, t, J=6.4 Hz), 5.19 (2H, s), 5.99 (1H, d,J=2.0 Hz), 7.01 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.10 (1H, d, J=1.6 Hz), 7.48(1H, d, J=8.4 Hz), 7.59 (1H, d, J=1.6 Hz), 7.74 (1H, d, J=5.2 Hz), 8.04(1H, s), 8.66 (1H, d, J=5.2 Hz), 13.86 (1H, s). [M+H] Calc'd forC₂₀H₂₀ClN₃O₄, 402. Found, 402.

Example 1122-[5-[[4-chloro-2-(2-methylpropoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-(2-methylpropoxy)phenyl]methanol

The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol(PREPARATION 7) and 1-bromo-2-methylpropane according to the procedurefor the preparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ1.04 (6H, d, J=6.8 Hz), 2.07-2.17 (1H, m), 2.29 (1H, s), 3.75 (2H, d,J=6.4 Hz), 4.65 (2H, d, J=4.8 Hz), 6.83 (1H, d, J=2.0 Hz), 6.90 (1H, dd,J=2.0 Hz, 8.0 Hz), 7.20 (1H, d, J=8.0 Hz).

B.2-[5-[[4-chloro-2-(2-methylpropoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-(2-methylpropoxy)phenyl]methanol according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ1.00 (6H, d, J=6.8 Hz), 2.06-2.12 (1H, m), 3.77 (2H, d, J=6.0 Hz), 5.24(2H, s), 5.77 (1H, d, J=2.0 Hz), 6.89 (1H, d, J=1.6 Hz), 6.95 (1H, dd,J=2.0 Hz, 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8Hz), 7.57 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H]Calc'd for C₂₀H₁₉ClN₄O₂, 383. Found, 383.

C.2-[5-[[4-chloro-2-(2-methylpropoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-(2-methylpropoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.88 (6H, d, J=6.4 Hz), 1.91-1.97 (1H, m),3.79 (2H, d, J=6.0 Hz), 5.19 (2H, s), 5.96 (1H, d, J=2.0 Hz), 7.01 (1H,dd, J=2.0 Hz, 8.4 Hz), 7.09 (1H, d, J=2.0 Hz), 7.48 (1H, d, J=8.0 Hz),7.55 (1H, d, J=1.6 Hz), 7.68 (1H, d, J=8.4 Hz), 7.96 (1H, s), 8.52 (1H,d, J=4.4 Hz). [M+H] Calc'd for C₂₀H₂₀ClN₃O₄, 402. Found, 402.

Example 1132-[5-[(4-chloro-2-propan-2-yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-chloro-2-propan-2-yloxyphenyl)methanol

The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol(PREPARATION 7) and isopropylbromide according to the procedure for thepreparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ 1.36 (6H,d, J=6.4 Hz), 2.40 (1H, s), 4.55-4.59 (1H, m), 4.61 (2H, s), 6.86 (1H,d, J=2.0 Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.18 (1H, d, J=7.6 Hz).

B.2-[5-[(4-chloro-2-propan-2-yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-propan-2-yloxyphenyl)methanol according to the procedure forthe preparation of Example 39, part C. ¹H NMR (400 MHz, DMSO-d₆): δ 1.34(6H, d, J=6.0 Hz), 4.56-4.62 (1H, m), 5.21 (2H, s), 5.77 (1H, d, J=1.6Hz), 6.90 (1H, d, J=1.2 Hz), 6.93 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.34 (1H,d, J=8.0 Hz), 7.39 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz),8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₉H₁₇ClN₄O₂,369. Found, 369.

C.2-[5-[(4-chloro-2-propan-2-yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-propan-2-yloxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.19 (6H, d, J=6.0 Hz), 4.66-4.72 (1H, m),5.17 (2H, s), 5.99 (1H, d, J=2.0 Hz), 6.99 (1H, dd, J=2.0 Hz, 8.0 Hz),7.13 (1H, d, J=2.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz),7.74 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.05 (1H, s), 8.66 (1H, d, J=4.8 Hz),13.87 (1H, s). [M+H] Calc'd for C₁₉H₁₈ClN₃O₄, 388. Found, 388.

Example 1142-[5-[(2-butan-2-yloxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2-butan-2-yloxy-4-chlorophenyl)methanol

The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol(PREPARATION 7) and 2-bromobutane according to the procedure for thepreparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ 0.98 (3H,t, J=7.6 Hz), 1.32 (3H, d, J=6.0 Hz), 1.65-1.79 (2H, m), 2.30 (1H, t,J=6.8 Hz), 4.32-4.40 (1H, m), 4.62 (2H, d, J=6.4 Hz), 6.85 (1H, d, J=1.6Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.19 (1H, d, J=8.4 Hz).

B.2-[5-[(2-butan-2-yloxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-butan-2-yloxy-4-chlorophenyl)methanol according to the procedure forthe preparation of Example 39, part C. [M+H] Calc'd for C₂₀H₁₉ClN₄O₂,383. Found, 383.

C.2-[5-[(2-butan-2-yloxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-butan-2-yloxy-4-chlorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.82 (3H, t, J=7.6 Hz), 1.14 (3H, d, J=6.0Hz), 1.50-1.59 (2H, m), 4.46-4.51 (1H, m), 5.15 (2H, s), 5.92 (1H, d,J=2.0 Hz), 6.98 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.11 (1H, d, J=1.6 Hz), 7.47(1H, d, J=7.6 Hz), 7.52 (1H, d, J=1.6 Hz), 7.64 (1H, d, J=4.8 Hz), 7.93(1H, s), 8.45 (1H, d, J=4.4 Hz). [M+H] Calc'd for C₂₀H₂₀ClN₃O₄, 402.Found, 402.

Example 1152-[5-[(4-chloro-2-ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-chloro-2-ethoxyphenyl)methanol

The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol(PREPARATION 7) and ethylbromide according to the procedure for thepreparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ 1.44 (3H,t, J=6.8 Hz), 2.24 (1H, s), 4.07 (2H, q, J=6.8 Hz), 4.64 (2H, s), 6.85(1H, d, J=1.6 Hz), 6.91 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.20 (1H, d, J=8.0Hz).

B.2-[5-[(4-chloro-2-ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-ethoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, DMSO-d₆): δ 1.42(3H, t, J=6.8 Hz), 4.09 (2H, q, J=6.8 Hz), 5.23 (2H, s), 5.79 (1H, d,J=1.6 Hz), 6.90 (1H, dd, J=2.0 Hz, 8.0 Hz), 6.95 (1H, dd, J=2.0 Hz, 8.0Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, m), 7.57 (1H, d, J=2.0 Hz), 8.05(1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₅ClN₄O₂, 355.Found, 355.

C.2-[5-[(4-chloro-2-ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-ethoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.26 (3H, t, J=6.8 Hz), 4.08 (2H, q, J=6.8Hz), 5.20 (2H, s), 6.01 (1H, d, J=2.0 Hz), 7.01 (1H, dd, J=2.0 Hz, 8.0Hz), 7.10 (1H, d, J=2.0 Hz), 7.48 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=2.0Hz), 7.74 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.05 (1H, s), 8.67 (1H, d, J=4.8Hz), 13.87 (1H, s). [M+H] Calc'd for C₁₈H₁₆ClN₃O₄, 374. Found, 374.

Example 1162-[5-[[4-chloro-2-(2-methoxyethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-(2-methoxyethoxy)phenyl]methanol

The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol(PREPARATION 7) and 2-methoxyethylbromide according to the procedure forthe preparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ 3.24(3H, s), 3.73-3.75 (2H, m), 4.16-4.18 (2H, m), 4.62 (2H, s), 6.87 (1H,d, J=1.6 Hz), 6.93 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.18 (1H, d, J=8.0 Hz).

B.2-[5-[[4-chloro-2-(2-methoxyethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-(2-methoxyethoxy)phenyl)methanol according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ3.39 (3H, s), 3.74 (2H, t, J=4.8 Hz), 4.18 (2H, t, J=4.8 Hz), 5.26 (2H,s), 5.81 (1H, s), 6.92 (1H, d, J=1.6 Hz), 6.98 (1H, dd, J=2.0 Hz, 8.0Hz), 7.35 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=5.2 Hz), 7.57 (1H, d, J=1.2Hz), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd forC₁₉H₁₇ClN₄O₃, 385. Found, 385.

C.2-[5-[[4-chloro-2-(2-methoxyethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-(2-methoxyethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.25 (3H, s), 3.61 (2H, t, J=4.4 Hz), 4.17(2H, t, J=4.4 Hz), 5.20 (2H, s), 6.00 (1H, d, J=2.0 Hz), 7.03 (1H, dd,J=2.0 Hz, 8.4 Hz), 7.16 (1H, d, J=1.6 Hz), 7.49 (1H, d, J=8.0 Hz), 7.59(1H, d, J=1.6 Hz), 7.74 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.06 (1H, s), 8.67(1H, d, J=5.2 Hz), 13.85 (1H, s). [M+H] Calc'd for C₁₉H₁₈ClN₃O₅, 404.Found, 404.

Example 1172-[5-[[4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methanol

To a solution of 5-chloro-2-(hydroxymethyl)phenol (943 mg, 5.95 mmol)and NaOH (3.5 mL, 6.54 mmol, 2M in water) in ethanol (10 mL) was added4-(bromomethyl)-1-fluorobenzene (1.13 g, 5.95 mmol) slowly, the mixturewas then stirred at room temperature overnight. Water was added to thereaction mixture, and extracted with ethyl acetate. The organic phasewas collected and washed with water, brine, and dried with anhydrousNa₂SO₄. The solvent was removed to give 900 mg of the title compound(57%). ¹H NMR (400 MHz, CDCl₃): δ 2.08 (1H, t, J=6.4 Hz), 4.67 (2H, d,J=6.4 Hz), 5.05 (2H, s), 6.93 (1H, d, J=1.2 Hz), 6.96 (1H, dd, J=1.6 Hz,8.0 Hz), 7.07-7.11 (2H, m), 7.25 (1H, d, J=6.0 Hz), 7.37-7.40 (2H, m).

B.2-[5-[[4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 5.07 (2H, s), 5.25 (2H, s), 5.73 (1H, d, J=1.6 Hz), 6.98-7.07(4H, m), 7.32-7.39 (4H, m), 7.55 (1H, d, J=1.6 Hz), 8.00 (1H, s), 8.67(1H, d, J=5.2 Hz). [M+H] Calc'd for C₂₃H₁₆ClFN₄O₂, 435. Found, 435.

C.2-[5-[[4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.17 (2H, s), 5.24 (2H, s), 5.99 (1H, s), 7.05(1H, d, J=8.0 Hz), 7.14 (2H, t, J=8.8 Hz), 7.21 (1H, s), 7.43 (2H, dd,J=5.6 Hz, 8.0 Hz), 7.52 (1H, d, J=8.0 Hz), 7.58 (1H, s), 7.73 (1H, d,J=5.2 Hz), 8.04 (1H, s), 8.65 (1H, d, J=5.6 Hz), 13.86 (1H, s). [M+H]Calc'd for C₂₃H₁₇ClFN₃O₄, 454. Found, 454.

Example 1182-[5-[[4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methanol

The title compound was prepared from 5-fluoro-2-(hydroxymethyl)phenoland 4-(bromomethyl)-1-fluorobenzene according to the procedure for thepreparation of Example 117, part A. ¹H NMR (400 MHz, CDCl₃): δ 2.07 (1H,t, J=6.8 Hz), 4.67 (2H, d, J=6.0 Hz), 5.05 (2H, s), 6.65-6.68 (2H, m),7.07-7.11 (2H, m), 7.24-7.28 (1H, m), 7.37-7.41 (2H, m).

B.2-[5-[[4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. [M+H] Calc'd forC₂₃H₁₆F₂N₄O₂, 419. Found, 419.

C.2-[5-[[4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.15 (2H, s), 5.22 (2H, s), 6.00 (1H, d, J=2.0Hz), 6.78-6.83 (1H, m), 7.03 (1H, t, J=2.4 Hz, 11.6 Hz), 7.12 (2H, t,J=8.8 Hz), 7.42 (2H, dd, J=5.2 Hz, 8.4 Hz), 7.53 (1H, t, J=8.0 Hz), 7.57(1H, d, J=2.0 Hz), 7.72 (1H, d, J=0.8 Hz, 4.8 Hz), 8.02 (1H, s), 8.62(1H, d, J=5.2 Hz). [M+H] Calc'd for C₂₃H₁₇F₂N₃O₄, 438. Found, 438.

Example 1192-[5-[[4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol

Charged (2-bromo-4-fluorophenyl)methanol (954 mg, 4.65 mmol),4-fluoro-1-vinylbenzene (1.14 g, 9.31 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.07mmol), Et₃N (942 mg, 9.31 mmol) and DMF (5 mL) to a sealed tube, themixture was then purged with nitrogen, heated to 150° C. for 3 h inmicrowave oven. The reaction mixture was filtered, the filtrate was thenextracted with ethyl acetate, concentrated and purified by flash columnchromatograph to give 569 mg of the title compound (50%). ¹H NMR (400MHz, CDCl₃): δ 1.60 (1H, t, J=6.4 Hz), 4.78 (2H, d, J=6.4 Hz), 6.93-7.08(4H, m), 7.31-7.35 (3H, m), 7.48-7.52 (2H, m).

B.2-[5-[[4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according tothe procedure for the preparation of Example 39, part C. ¹H NMR (400MHz, CDCl₃): δ 5.31 (2H, s), 5.82 (1H, d, J=1.6 Hz), 6.96-7.04 (4H, m),7.22-7.23 (1H, m), 7.34-7.41 (5H, m), 7.59 (1H, d, J=1.6 Hz), 7.90 (1H,s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₂₄H₁₆F₂N₄O, 415. Found,415.

C.2-[5-[[4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.45 (2H, s), 6.13 (1H, d, J=1.6 Hz),7.09-7.25 (4H, m), 7.38 (1H, d, J=16.0 Hz), 7.51-7.65 (6H, m), 7.98 (1H,s), 8.50 (1H, d, J=5.6 Hz), 13.83 (1H, s). [M+H] Calc'd forC₂₄H₁₇F₂N₃O₃, 434. Found, 434.

Example 1202-[5-[[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2-bromo-4-chlorophenyl)methanol

Added BH₃ (1M in THF, 40 mL) to a solution of 2-bromo-4-chlorobenzoicacid (3.14 g, 13.33 mmol) in THF (3 mL) drop wise at 0° C. The reactionmixture was stirred at room temperature overnight. Extracted with ethylacetate twice, and washed the organic phase with brine and dried withanhydrous Na₂SO₄, concentrated to give the title compound (2.5 g, 85%).¹H NMR (300 MHz, CDCl₃): δ 4.72 (2H, s), 7.32 (1H, dd, J=1.8 Hz, 8.1Hz), 7.43 (1H, d, J=8.1 Hz), 7.56 (1H, d, J=2.1 Hz).

B. [4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol

The title compound was prepared from (2-bromo-4-chlorophenyl)methanoland 4-fluoro-1-vinylbenzene according to the procedure for thepreparation of Example 119, part B. ¹H NMR (400 MHz, CDCl₃): δ 1.72 (1H,t, J=5.6 Hz), 4.77 (2H, d, J=5.2 Hz), 6.98-7.08 (3H, m), 7.22-7.34 (3H,m), 7.47-7.50 (2H, m), 7.60 (1H, d, J=1.6 Hz).

C.2-[5-[[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according tothe procedure for the preparation of Example 39, part C. ¹H NMR (400MHz, CDCl₃): δ 5.31 (2H, s), 5.81 (1H, d, J=2.0 Hz), 6.96-7.04 (3H, m),7.18-7.28 (3H, m), 7.35-7.39 (3H, m), 7.59 (1H, d, J=1.6 Hz), 7.63 (1H,d, J=2.4 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₂₄H₁₆ClFN₄O, 431. Found, 431.

D.2-[5-[[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.45 (2H, s), 6.11 (1H, d, J=2.0 Hz),7.16-7.27 (3H, m), 7.34-7.38 (2H, m), 7.53-7.63 (5H, m), 7.80 (1H, d,J=2.0 Hz), 7.98 (1H, s), 8.48 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₂₄H₁₇ClFN₃O₃, 450. Found, 450.

Example 1212-[5-[[4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol

Charged [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol (568mg, 2.31 mmol, EXAMPLE 119, part A), Pd/C (65 mg) and methanol (6 mL) toa flask, the mixture was then purged with hydrogen, stirred at roomtemperature overnight. It was then filtered, filtrate concentrated togive a residue which was purified by flash column chromatograph to give214 mg of the title compound (37%). ¹H NMR (400 MHz, CDCl₃): δ 1.42 (1H,t, J=5.2 Hz), 2.83-2.98 (4H, m), 4.59 (2H, d, J=5.6 Hz), 6.88-6.98 (4H,m), 7.08-7.11 (2H, m), 7.29-7.33 (1H, m).

B.2-[5-[[4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 2.86-2.98 (4H, m), 5.05 (2H, s), 5.73 (1H, d, J=2.0 Hz),6.90-78.01 (6H, m), 7.33-7.39 (2H, m), 7.59 (1H, d, J=1.6 Hz), 7.95 (1H,s), 8.56 (1H, d, J=4.4 Hz). [M+H] Calc'd for C₂₄H₁₈F₂N₄O, 417. Found,417.

C.2-[5-[[4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.80-2.93 (4H, m), 5.25 (2H, s), 6.09 (1H, d,J=1.6 Hz), 7.00-7.12 (6H, m), 7.56 (1H, dd, J=6.4 Hz, 8.4 Hz), 7.62 (1H,d, J=1.6 Hz), 7.68 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.01 (1H, s), 8.55 (1H,d, J=4.8 Hz). [M+H] Calc'd for C₂₄H₁₉F₂N₃O₃, 436. Found, 436.

Example 1222-[5-[[4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol

The title compound was prepared from[4-chloro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol (EXAMPLE 120,part B) according to the procedure for the preparation of Example 121,part A. ¹H NMR (400 MHz, CDCl₃): δ 1.46 (1H, s), 2.84-2.94 (4H, m), 4.54(2H, d, J=4.0 Hz), 6.84-6.98 (2H, m), 7.08-7.11 (2H, m), 7.18-7.20 (2H,m), 7.29 (1H, d, J=8.0 Hz).

B.2-[5-[[4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 2.86-2.95 (4H, m), 5.03 (2H, s), 5.70 (1H, d, J=2.0 Hz),6.91-7.01 (4H, m), 7.21-7.24 (2H, m), 7.33-7.36 (2H, m), 7.58 (1H, d,J=1.6 Hz), 7.96 (1H, s), 8.57 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'dfor C₂₄H₁₈ClFN₄O, 433. Found, 433.

C.2-[5-[[4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.80-2.93 (4H, m), 5.27 (2H, s), 6.08 (1H, d,J=2.0 Hz), 7.03 (2H, t, J=9.1 Hz), 7.12 (2H, dd, J=6.0 Hz, 8.4 Hz), 7.29(1H, dd, J=2.4 Hz, 8.4 Hz), 7.33 (1H, d, J=2.0 Hz), 7.55 (1H, d, J=8.4Hz), 7.62 (1H, d, J=2.0 Hz), 7.69 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.02 (1H,s), 8.56 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₂₄H₁₉ClFN₃O₃, 452. Found,452.

Example 1232-[5-(2,3-dihydro-1-benzofuran-7-ylmethoxy)pyrazol-1-yl]pyridine-4-carboxylicacid A. 2,3-dihydro-1-benzofuran-7-ylmethanol

Added BH₃ (1M in THF, 9 mL) to a solution of2,3-dihydro-1-benzofuran-7-carboxylic acid (481 mg, 2.93 mmol) in THF (7mL) drop wise at 0° C., thereto, the mixture was stirred at roomtemperature overnight. Extracted with ethyl acetate twice, and washedthe organic phase with brine and dried with anhydrous Na₂SO₄,concentrated to give the title compound (340 mg, 77%). ¹H NMR (400 MHz,CDCl₃): δ 2.09 (1H, s), 3.22 (2H, t, J=8.8 Hz), 4.61 (2H, t, J=8.8 Hz),4.67 (2H, s), 6.83 (1H, t, J=7.6 Hz), 7.08 (1H, d, J=7.2 Hz), 7.14 (1H,d, J=7.2 Hz).

B.2-[5-(2,3-dihydro-1-benzofuran-7-ylmethoxy)pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and2,3-dihydro-1-benzofuran-7-ylmethanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 3.27 (2H,q, J=8.8 Hz), 4.68 (2H, q, J=8.8 Hz), 5.21 (2H, s), 5.83 (1H, d, J=2.0Hz), 6.86 (1H, q, J=7.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.22 (1H, d, J=7.2Hz), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H,s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₄N₄O₂, 319. Found,319.

C.2-[5-(2,3-dihydro-1-benzofuran-7-ylmethoxy)pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-(2,3-dihydro-1-benzofuran-7-ylmethoxy)pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.17 (2H, q, J=8.4 Hz), 4.55 (2H, q, J=8.4Hz), 5.11 (2H, s), 5.93 (1H, s), 6.81 (1H, t, J=7.2 Hz), 7.18-7.20 (2H,m), 7.48 (1H, s), 7.62 (1H, d, J=4.8 Hz), 7.86 (1H, s), 8.39 (1H, d,J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₅N₃O₄, 338. Found, 338.

Example 124 2-[5-[(2,2-dimethyl-3H-1-benzofuran-7-yl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid A.2-[5-[(2,2-dimethyl-3H-1-benzofuran-7-yl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2,2-dimethyl-3H-1-benzofuran-7-yl)methanol according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ1.48 (6H, s), 3.03 (2H, s), 5.21 (2H, s), 5.83 (1H, d, J=2.0 Hz), 6.83(1H, q, J=8.0 Hz), 7.13 (1H, d, J=7.2 Hz), 7.18 (1H, d, J=8.0 Hz), 7.37(1H, dd, J=0.8 Hz, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.07 (1H, s), 8.70(1H, d, J=4.8 Hz). [M+H] Calc'd for C₂₀H₁₈N₄O₂, 347. Found, 347

B.2-[5-[(2,2-dimethyl-3H-1-benzofuran-7-yl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2,2-dimethyl-3H-1-benzofuran-7-yl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.38 (6H, s), 3.00 (2H, s), 5.14 (2H, s), 6.00(1H, d, J=2.0 Hz), 6.70-6.81 (1H, m), 7.15-7.22 (2H, m), 7.56 (1H, d,J=2.0 Hz), 7.74 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.05 (1H, s), 8.66 (1H, d,J=5.2 Hz). [M+H] Calc'd for C₂₀H₁₉N₃O₄, 366. Found, 366.

Example 1252-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 4-(hydroxymethyl)-3-methylbenzonitrile

Charge methyl 4-cyano-2-methylbenzoate (627 mg, 3.57 mmol), THF (12 mL)and ethanol (12 mL) to a flask, followed by CaCl₂ (418 mg, 3.57 mmol)and NaBH₄ (265 mg, 7.16 mmol). The mixture was then stirred at roomtemperature overnight. Water was added, and the mixture was extractedwith ethyl acetate. The organic extract was concentrated and purified byflash column chromatograph to give 325 mg of the title compound (62%).¹H NMR (300 MHz, CDCl₃): δ 1.83 (1H, t, J=5.4 Hz), 2.33 (3H, s), 4.75(2H, d, J=5.4 Hz), 7.43 (1H, s), 7.52-7.56 (2H, m).

B. methyl2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

To a mixture of methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate(PREPARATION 6, 112 mg, 0.51 mmol),4-(hydroxymethyl)-3-methylbenzonitrile (83 mg, 0.56 mmol), PPh₃ (268 mg,1.02 mmol) and THF (6 mL) cooled in ice-water bath, DIAD (207 mg, 1.02mmol) was added. The mixture was stirred overnight at room temperature.It was then concentrated and purified by flash column chromatograph togive 112 mg of the title compound (63%). [M+H] Calc'd for C₁₉H₁₆N₄O₃,349. Found, 349.

C.2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

Charged methyl2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate(112 mg, 0.32 mmol), LiOH.H₂O (14 mg, 0.32 mmol), water (2 mL) and THF(2 mL) to a flask, then the mixture was stirred at room temperature for30 min, added another 2 mL water, and the mixture was washed with ethylacetate twice (6 mL×2). The aqueous phase was acidified with 1N HCl(pH=3), filtered and dried the solid to give the title compound. ¹H NMR(300 MHz, DMSO-d₆): δ 2.37 (3H, s), 5.37 (2H, s), 6.10 (1H, d, J=1.8Hz), 7.62 (1H, d, J=1.5 Hz), 7.70-7.77 (4H, m), 8.08 (1H, s), 8.68 (1H,d, J=5.4 Hz). [M+H] Calc'd for C₁₈H₁₄N₄O₃, 335. Found, 335.

Example 1262-[5-[(4-cyano-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 4-bromo-2-ethylbenzoic acid

To a yellow solution of 2,2,6,6-TMPH (8.30 g, 58.88 mmol) in THF (9 mL)was added n-BuLi (25 mL) slowly at −78° C. under protection of nitrogen.Thereto, the mixture was warmed up to room temperature, stirred at thistemperature for an hour, and then cooled to −78° C. again. A solution of4-bromo-2-methylbenzoic acid (6.0 g, 28.04 mmol) in THF (60 mL) wasadded slowly, kept stirring at this temperature for an hour, added MeI(7.96 g, 56.07 mmol) solution (in 35 mL THF), the mixture above was thenstirred overnight at room temperature. LCMS showed the reaction wascompleted. Water was added, the mixture was then washed with ethylacetate. The aqueous phase was acidified to pH=1, extracted with ethylacetate twice, and concentrated the organic phase to a residue which wastrituated with PE/EA=1/1 to give 4.28 g of the title compound (67%).

B. methyl 4-bromo-2-ethylbenzoate

Charged compound 4-bromo-2-ethylbenzoic acid (2.05 g, 9.58 mmol) andmethanol (20 mL) to a flask, SOCl₂ (3.42 g, 28.74 mmol) was added slowlyat 0° C. The reaction mixture was heated to 70° C. for three hour.Solvent was removed and the residue was dissolved in CH₂Cl₂, filtered,the filtrate was concentrated to a residue which was purified by flashcolumn chromatograph to give 1.9 g of the title compound (87%).

C. methyl 4-cyano-2-ethylbenzoate

Charged methyl 4-bromo-2-ethylbenzoate (1.9 g, 7.85 mmol), Zn(CN)₂ (1.48g, 12.56 mmol), Pd (PPh₃)₄ (1.0 g, 0.94 mmol) and DMF (30 mL) to aflask, the system was then purged with nitrogen and heated at 100° C.for 6 h. The reaction mixture was then filtered. The filtrate wasextracted with ethyl acetate and concentrated the organic phase forflash column chromatograph to give 0.6 g of the title compound (40%). ¹HNMR (400 MHz, CDCl₃): δ 1.24 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz),3.92 (3H, s), 7.52-7.54 (1H, m), 7.57 (1H, s), 7.90 (1H, d, J=8.0 Hz).

D. 3-ethyl-4-(hydroxymethyl)benzonitrile

The title compound was prepared from methyl 4-cyano-2-ethylbenzoateaccording to the procedure for the preparation of Example 125, part A.¹H NMR (300 MHz, CDCl₃): δ 1.23 (3H, t, J=5.7 Hz), 1.63 (1H, s), 2.67(2H, q, J=5.7 Hz), 4.68 (2H, s), 7.16-7.19 (2H, m), 7.30 (1H, d, J=6.0Hz)

E. methyl2-[5-[(4-cyano-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from methyl2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and3-ethyl-4-(hydroxymethyl)benzonitrile according to the procedure for thepreparation of Example 125, part B. ¹H NMR (400 MHz, CDCl₃): δ 1.26 (3H,t, J=7.6 Hz), 2.73 (2H, q, J=7.6 Hz), 3.96 (3H, s), 5.28 (2H, s), 5.77(1H, d, J=1.2 Hz), 7.53-7.67 (4H, m), 7.77 (1H, d, J=4.8 Hz), 8.31 (1H,s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₂₀H₁₈N₄O₃, 363. Found,363.

F.2-[5-[(4-cyano-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from methyl2-[5-[(4-cyano-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylateaccording to the procedure for the preparation of Example 125, part C.¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (3H, t, J=7.6 Hz), 2.73 (2H, q, J=7.6Hz), 5.39 (2H, s), 6.10 (1H, s), 7.62 (1H, s), 7.69-7.76 (4H, m), 8.08(1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₉H₁₆N₄O₃, 349.Found, 349.

Example 1272-[5-[(4-chloro-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 4-chloro-2-ethylbenzoic acid

To a yellow solution of 2,2,6,6-TMPH (5.45 g, 38.69 mmol) in THF (6 mL)was added n-BuLi (16 mL) slowly at −78° C. under protection of nitrogen,thereto, the mixture was warmed up to room temperature, stirred at thistemperature for an hour, and then cooled to −78° C. again, a solution of4-chloro-2-methylbenzoic acid (3.0 g, 17.58 mmol) in THF (30 mL) wasadded slowly, kept stirring at this temperature for an hour, added MeI(5.49 g, 38.69 mmol) solution (in 20 mL THF), the mixture above was thenstirred overnight at room temperature. LCMS showed the completion of thereaction, added water, the mixture was then washed with ethyl acetate,the aqueous phase was acidified to pH=1, extracted with ethyl acetatetwice, and concentrated the organic phase, washed the residue withPE/EA=1/1 to give 1.5 g of the title compound (46%).

B. (4-chloro-2-ethylphenyl)methanol

The title compound was prepared from 4-chloro-2-ethylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (300 MHz, CDCl₃): δ 1.23 (3H, t, J=5.7 Hz), 1.63 (1H, s), 2.67(2H, q, J=5.7 Hz), 4.68 (2H, s), 7.16-7.19 (2H, m), 7.30 (1H, d, J=6.0Hz).

C.2-[5-[(4-chloro-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-chloro-2-ethylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H,t, J=7.6 Hz), 2.70 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.78 (1H, d, J=2.0Hz), 7.20 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.25 (1H, d, J=1.6 Hz), 7.36 (1H,d, J=8.4 Hz), 7.39 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.59 (1H, d, J=2.0 Hz),7.99 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₅ClN₄O, 339.Found, 339.

D.2-[5-[(4-chloro-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-chloro-2-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.12 (3H, t, J=7.6 Hz), 2.69 (2H, q, J=7.6Hz), 5.28 (2H, s), 6.10 (1H, d, J=2.0 Hz), 6.27 (1H, dd, J=2.4 Hz, 8.4Hz), 7.31 (1H, d, J=2.0 Hz), 7.53 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=2.0Hz), 7.74 (1H, dd, J=1.2 Hz, 4.8 Hz), 8.05 (1H, s), 8.64 (1H, d, J=4.8Hz). [M+H] Calc'd for C₁₈H₁₆ClN₃O₃, 358. Found, 358.

Example 1282-[5-[(4-fluoro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-fluoro-2-methylphenyl)methanol

The title compound was prepared from 4-fluoro-2-methylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.

B.2-[5-[(4-fluoro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-fluoro-2-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.38 (3H,s), 5.17 (2H, s), 5.78 (1H, d, J=1.6 Hz), 6.89-6.95 (2H, m), 7.34-7.39(2H, m), 7.58 (1H, d, J=2.4 Hz), 7.98 (1H, s), 8.67 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₇H₁₃FN₄O, 309. Found, 309.

C.2-[5-[(4-fluoro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-fluoro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.35 (3H, s), 5.26 (2H, s), 6.10 (1H, d, J=1.2Hz), 7.00-7.10 (2H, m), 7.51-7.54 (1H, m), 7.61 (1H, d, J=1.2 Hz), 7.74(1H, d, J=4.4 Hz), 8.04 (1H, s), 8.65 (1H, d, J=5.2 Hz). [M+H] Calc'dfor C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 1292-[5-[(2-ethyl-4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 2-ethyl-4-fluorobenzoic acid

The title compound was prepared from 4-fluoro-2-methylbenzoic acidaccording to the procedure for the preparation of Example 126, part A.¹H NMR (300 MHz, DMSO-d₆): δ 1.15 (3H, t, J=7.5 Hz), 2.94 (2H, q, J=7.5Hz), 7.07-7.20 (2H, m), 7.86 (1H, dd, J=6.3 Hz, 8.7 Hz), 12.91 (1H, s).

B. (2-ethyl-4-fluorophenyl)methanol

The title compound was prepared from 2-ethyl-4-fluorobenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (300 MHz, CDCl₃): δ 1.24 (3H, t, J=7.5 Hz), 2.71 (2H, q, J=7.5Hz), 4.67 (2H, s), 6.84-6.95 (2H, m), 7.31 (1H, dd, J=6.3 Hz, 8.4 Hz).

C.2-[5-[(2-ethyl-4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-ethyl-4-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H,t, J=7.6 Hz), 2.72 (2H, q, J=7.6 Hz), 5.20 (2H, s), 5.79 (1H, d, J=2.0Hz), 6.89-7.00 (2H, m), 7.36-7.40 (2H, m), 7.59 (1H, d, J=2.0 Hz), 7.98(1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₅FN₄O, 323.Found, 323.

D.2-[5-[(2-ethyl-4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-ethyl-4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.12 (3H, t, J=7.6 Hz), 2.70 (2H, q, J=7.6Hz), 5.26 (2H, s), 6.10 (1H, d, J=2.0 Hz), 7.00-7.11 (2H, m), 7.54 (1H,dd, J=6.4 Hz, 8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 7.73-7.74 (1H, m), 8.03(1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₆FN₃O₃, 342.Found, 342.

Example 1302-[5-[(2-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2-chloro-4-methylphenyl)methanol

The title compound was prepared from 2-chloro-4-methylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (400 MHz, CDCl₃): δ 1.90 (1H, s), 2.33 (3H, s), 4.74 (2H, s),7.07 (1H, d, J=7.6 Hz), 7.19 (1H, s), 7.33 (1H, d, J=7.6 Hz).

B.2-[5-[(2-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-chloro-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.35 (3H,s), 5.30 (2H, s), 5.80 (1H, d, J=1.6 Hz), 7.10 (1H, d, J=8.4 Hz), 7.25(1H, d, J=3.2 Hz), 7.40 (2H, dd, J=1.2 Hz, 5.2 Hz), 7.58 (1H, d, J=2.4Hz), 8.06 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₇H₁₃ClN₄O,325. Found, 325.

C.2-[5-[(2-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.31 (3H, s), 5.28 (2H, s), 6.05 (1H, d, J=2.0Hz), 7.19 (1H, d, J=7.6 Hz), 7.33 (1H, s), 7.55 (1H, d, J=7.6 Hz), 7.60(1H, d, J=2.0 Hz), 7.75 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.07 (1H, s), 8.67(1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₄ClN₃O₃, 344. Found, 344.

Example 1312-[5-[(2-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2-fluoro-4-methylphenyl)methanol

The title compound was prepared from 2-fluoro-4-methylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (300 MHz, CDCl₃): δ 1.71 (1H, t, J=6.0 Hz), 2.34 (3H, s), 4.71(2H, d, J=6.0 Hz), 6.85-6.96 (2H, m), 7.24-7.30 (1H, m).

B.2-[5-[(2-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-fluoro-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.36 (3H,s), 5.26 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=11.2 Hz), 6.98(1H, d, J=8.0 Hz), 7.31-7.35 (1H, m), 7.38 (1H, dd, J=1.2 Hz, 4.8 Hz),7.57 (1H, d, J=1.6 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H]Calc'd for C₁₇H₁₃FN₄O, 309. Found, 309.

C.2-[5-[(2-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.31 (3H, s), 5.26 (2H, s), 6.05 (1H, d, J=2.0Hz), 7.02-7.07 (2H, m), 7.47 (1H, t, J=7.6 Hz), 7.60 (1H, d, J=1.6 Hz),7.74 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.04 (1H, s), 8.65 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 1322-[5-[(2,4-dimethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(2,4-dimethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2,4-dimethylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. [M+H] Calc'd for C₁₈H₁₆N₄O, 305.Found, 305.

B. 2-[5-[(2,4-dimethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2,4-dimethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.25 (3H, s), 2.29 (3H, s), 5.21 (2H, s), 6.06(1H, d, J=2.0 Hz), 6.99 (1H, d, J=8.0 Hz), 7.02 (1H, s), 7.33 (1H, d,J=7.2 Hz), 7.59 (1H, d, J=1.6 Hz), 7.73-7.74 (1H, m), 8.03 (1H, s), 8.65(1H, d, J=4.8 Hz), 13.83 (1H, s). [M+H] Calc'd for C₁₈H₁₇N₃O₃, 324.Found, 324.

Example 1332-[5-[(2-methoxy-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (2-methoxy-4-methylphenyl)methanol

The title compound was prepared from 2-methoxy-4-methylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (300 MHz, CDCl₃): δ 2.35 (3H, s), 3.85 (3H, s), 4.64 (2H, s),6.70 (1H, s), 6.74 (1H, d, J=5.7 Hz), 7.13 (1H, d, J=5.7 Hz).

B.2-[5-[(2-methoxy-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-methoxy-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 3.37 (3H,s), 3.89 (3H, s), 5.23 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.76-6.79 (2H,m), 7.24-7.26 (1H, m), 7.37 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d,J=1.6 Hz), 8.08 (1H, s), 8.70 (1H, d, J=4.4 Hz). [M+H] Calc'd forC₁₈H₁₆N₄O₂, 321. Found, 321.

C.2-[5-[(2-methoxy-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-methoxy-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.30 (3H, s), 3.78 (3H, s), 5.17 (2H, s), 5.99(1H, d, J=1.6 Hz), 6.76 (1H, d, J=7.6 Hz), 6.86 (1H, s), 7.32 (1H, d,J=7.6 Hz), 7.58 (1H, d, J=1.6 Hz), 7.74 (1H, dd, J=0.8 Hz, 4.8 Hz), 8.06(1H, s), 8.66 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₅H₁₇N₃O₄, 340.Found, 340.

Example 1342-[5-[(2-cyano-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 2-cyano-4-methylbenzoate

The title compound was prepared from methyl 2-bromo-4-methylbenzoateaccording to the procedure for the preparation of Example 126, part C.¹H NMR (400 MHz, CDCl₃): δ 2.45 (3H, s), 3.98 (3H, s), 7.46 (1H, d,J=6.0 Hz), 7.60 (1H, s), 8.03 (1H, d, J=6.0 Hz).

B. 2-(hydroxymethyl)-5-methylbenzonitrile

The title compound was prepared from methyl 2-cyano-4-methylbenzoateaccording to the procedure for the preparation of Example 125, part A.¹H NMR (300 MHz, CDCl₃): δ 2.44 (3H, s), 5.26 (2H, s), 7.27 (1H, d,J=7.5 Hz), 7.37 (1H, d, J=8.1 Hz), 7.67 (1H, s).

C. methyl2-[5-[(2-cyano-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate

The title compound was prepared from methyl2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and2-(hydroxymethyl)-5-methylbenzonitrile according to the procedure forthe preparation of Example 125, part B. ¹H NMR (400 MHz, CDCl₃): δ 3.40(3H, s), 3.97 (3H, s), 5.40 (2H, s), 5.83 (1H, d, J=1.2 Hz), 7.43 (1H,d, J=8.8 Hz), 7.50 (1H, s), 7.58-7.62 (2H, m), 7.76 (1H, d, J=5.2 Hz),8.33 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₉H₁₆N₄O₃, 349.Found, 349.

D.2-[5-[(2-cyano-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from methyl2-[5-[(2-cyano-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylateaccording to the procedure for the preparation of Example 125, part C.¹H NMR (400 MHz, DMSO-d₆): δ 2.35 (3H, s), 5.38 (2H, s), 6.08 (1H, d,J=1.2 Hz), 7.55 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=1.6 Hz), 7.66 (1H, d,J=7.6 Hz), 7.71 (1H, s), 7.74 (1H, d, J=5.2 Hz), 8.04 (1H, s), 8.65 (1H,d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₄N₄O₃, 335. Found, 335.

Example 1352-[5-[(2-ethyl-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 2-ethenyl-4-methylbenzoate

A mixture of methyl 2-bromo-4-methylbenzoate (1.06 g, 4.63 mmol),vinyltrifluoroborate potassium salt (621 mg, 4.63 mmol), Pd(dppf)Cl₂(203 mg, 0.28 mmol) and TEA (1.40 g, 13.89 mmol) in n-PrOH (11 mL) waspurged with nitrogen, and heated to 100° C. for 2 h. It was then cooledto room temperature and filtered, the filtrate was extracted with ethylacetate twice. Organic extract was concentrated and purified by flashcolumn chromatograph to give 500 mg of the title compound (60%). ¹H NMR(400 MHz, CDCl₃): δ 2.40 (3H, s), 3.88 (3H, s), 5.33 (1H, dd, J=1.2 Hz,10.8 Hz), 5.62 (1H, dd, J=1.2 Hz, 17.6 Hz), 7.12 (1H, d, J=8.0 Hz), 7.37(1H, s), 7.48 (1H, dd, J=10.8 Hz, 17.6 Hz), 7.80 (1H, d, J=8.0 Hz).

B. methyl 2-ethyl-4-methylbenzoate

Charged compound methyl 2-ethenyl-4-methylbenzoate (773 mg, 4.42 mmol),Pd/C (100 mg) and methanol (14 mL) to a flask, the mixture was thenpurged with H₂, and stirred at room temperature overnight. It was thenfiltered, filtrated concentrated to give the title compound (646 mg,83%). ¹H NMR (300 MHz, CDCl₃): δ 1.22 (3H, t, J=7.5 Hz), 2.36 (3H, s),2.95 (2H, q, J=7.5 Hz), 3.87 (3H, s), 7.04 (1H, d, J=8.1 Hz), 7.07 (1H,s), 7.78 (1H, d, J=8.1 Hz).

C. (2-ethyl-4-methylphenyl)methanol

To a solution of compound methyl 2-ethyl-4-methylbenzoate (646 mg, 3.65mmol) in THF (6 mL) cooled to −50° C., was added LiAlH₄ (277 mg, 7.30mmol) in portions. The mixture was stirred at this temperature for 1 h.Added water (0.3 mL) slowly, followed by NaOH (aq, 10%, 0.3 mL) andwater (0.9 mL), the resulting mixture was filtered and washed with THF,concentrated the filtrate to give 518 mg of the title compound (95%). ¹HNMR (400 MHz, CDCl₃): δ 1.23 (3H, t, J=7.2 Hz), 1.54 (1H, s), 2.33 (3H,s), 2.68 (2H, q, J=7.6 Hz), 4.67 (2H, s), 7.01 (1H, d, J=8.0 Hz), 7.03(1H, s), 7.23 (1H, d, J=7.6 Hz).

D.2-[5-[(2-ethyl-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-ethyl-4-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.20 (3H,t, J=7.6 Hz), 2.35 (3H, s), 2.68 (2H, q, J=7.6 Hz), 5.21 (2H, s), 5.79(1H, d, J=1.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.07 (1H, s), 7.27 (1H, d,J=8.4 Hz), 7.36 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz),7.96-7.97 (1H, s), 8.66 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd forC₁₉H₁₈N₄O, 319. Found, 319.

E.2-[5-[(2-ethyl-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-ethyl-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.10 (3H, t, J=7.6 Hz), 2.27 (3H, s), 2.64(2H, q, J=7.6 Hz), 5.22 (2H, s), 6.07 (1H, d, J=2.0 Hz), 7.00 (1H, d,J=7.6 Hz), 7.05 (1H, s), 7.34 (1H, d, J=7.6 Hz), 7.59 (1H, d, J=2.0 Hz),7.72 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.02 (1H, s), 8.62 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₉H₁₉N₃O₃, 338. Found, 338.

Example 1362-[5-[[4-chloro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-2-(1-phenylethoxy)phenyl]methanol

Charged 5-chloro-2-(hydroxymethyl)phenol (787 mg, 4.96 mmol),(bromoethyl)benzene (1.01 g, 5.46 mmol), K₂CO₃ (1.37 g, 9.93 mmol) andDMF (8 mL) to a flask, heated to 100° C. overnight. Poured into icewater, and extracted with ethyl acetate twice, and washed the organicphase with water twice, brine and dried with anhydrous Na₂SO₄. Solventwas then removed and purified by flash column chromatograph to give 1.0g of the title compound (77%).

B.2-[5-[[4-chloro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-2-(1-phenylethoxy)phenyl]methanol according to the procedurefor the preparation of Example 39, part C. [M+H] Calc'd forC₂₄H₁₉ClN₄O₂, 431. Found, 431.

C.2-[5-[[4-chloro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (300 MHz, DMSO-d₆): δ 1.45 (3H, d, J=6.6 Hz), 5.25-5.33 (2H, m),5.57-5.63 (1H, m), 6.05 (1H, d, J=1.8 Hz), 6.93-6.95 (2H, m), 7.21-7.35(5H, m), 7.48 (1H, d, J=8.1 Hz), 7.61 (1H, d, J=1.2 Hz), 7.74-7.56 (1H,m), 8.08 (1H, s), 8.43 (1H, d, J=1.8 Hz). [M+H] Calc'd for C₂₄H₂₀ClN₃O₄,450. Found, 450.

Example 1372-[5-[[4-fluoro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-fluoro-2-(1-phenylethoxy)phenyl]methanol

The title compound was prepared from 5-fluoro-2-hydroxymethyl)phenol and(bromoethyl)benzene according to the procedure for the preparation ofExample 136, part A.

B.2-[5-[[4-fluoro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-fluoro-2-(1-phenylethoxy)phenyl]methanol according to the procedurefor the preparation of Example 39, part C. [M+H] Calc'd for C₂₄H₁₉FN₄O₂,415. Found, 415.

C.2-[5-[[4-fluoro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-fluoro-2-(1-phenylethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (300 MHz, DMSO-d₆): δ 1.45 (3H, d, J=6.6 Hz), 5.24-5.32 (2H, m),5.53-5.60 (1H, m), 6.07 (1H, d, J=2.1 Hz), 6.67-6.78 (2H, m), 7.21-7.34(5H, m), 7.50 (1H, t, J=7.8 Hz), 7.60-7.62 (1H, m), 7.74-7.75 (1H, m),8.07 (1H, s), 8.67 (1H, d, J=5.1 Hz). [M+H] Calc'd for C₂₄H₂₀FN₃O₄, 434.Found, 434.

Example 1382-[5-[[4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 2-chloro-5-(hydroxymethyl)phenol

The title compound was prepared from 4-chloro-3-hydroxybenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (300 MHz, CDCl₃): δ 4.39 (2H, d, J=5.7 Hz), 5.18 (1H, t, J=5.7Hz), 6.70-6.73 (1H, m), 6.94 (1H, s), 7.23 (1H, d, J=7.8 Hz), 10.03 (1H,s).

B. [4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methanol

The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenoland 4-(bromomethyl)-1-fluorobenzene according to the procedure for thepreparation of Example 117, part A. ¹H NMR (400 MHz, CDCl₃): δ 1.71 (1H,t, J=6.0 Hz), 4.65 (2H, d, J=6.4 Hz), 5.12 (2H, s), 6.88-6.90 (1H, m),7.02 (1H, d, J=2.0 Hz), 7.05-7.10 (2H, m), 7.35 (1H, d, J=8.0 Hz),7.43-7.46 (2H, m).

C.2-[5-[[4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 5.10 (2H, s), 5.18 (2H, s), 5.68 (1H, d, J=1.6 Hz), 6.97 (1H,dd, J=1.2 Hz, 8.0 Hz), 7.03-7.07 (3H, m), 7.39-7.43 (4H, m), 7.55 (1H,d, J=1.6 Hz), 8.04 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd forC₂₃H₁₆ClFN₄O₂, 435. Found, 435.

D.2-[5-[[4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.18 (2H, s), 5.24 (2H, s), 5.92 (1H, s),7.04-7.07 (1H, m), 7.19-7.23 (2H, m), 7.39 (1H, s), 7.44 (1H, d, J=8.4Hz), 7.51-7.54 (3H, m), 7.65 (1H, d, J=6.4 Hz), 7.96 (1H, s), 8.43 (1H,d, J=4.8 Hz). [M+H] Calc'd for C₂₃H₁₇ClFN₃O₄, 454. Found, 454.

Example 1392-[5-[[4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-fluoro-3-[(4-fluorophenyl)methoxy]benzoate

Charge methyl 4-fluoro-3-hydroxybenzoate (519 mg, 3.05 mmol),4-(bromomethyl)-1-fluorobenzene (577 mg, 3.05 mmol), K₂CO₃ (843 mg, 6.10mmol) and ethanol (10 mL) to a flask. The mixture was then stirred atroom temperature overnight. Water was added to the reaction mixture at0° C., filtered, and the solid dried and purified by flash columnchromatograph to give 571 mg of the title compound (67%). ¹H NMR (400MHz, CDCl₃): δ 3.90 (3H, s), 5.13 (2H, s), 7.06-7.15 (3H, m), 7.41-7.45(2H, m), 7.63-7.67 (1H, m), 7.71 (1H, dd, J=2.0 Hz, 8.4 Hz).

B. [4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methanol

To a solution of methyl 4-fluoro-3-[(4-fluorophenyl)methoxy]benzoate(571 mg, 2.05 mmol) in THF (6 mL) cooled to −50° C., was added LiAlH₄solution (4.6 mL, 4.11 mmol, 1.0 M in THF) drop wise. Thereto, themixture was stirred at this temperature for 1 h. Added water (0.2 mL)slowly, followed by NaOH (aq, 10%, 0.2 mL) and water (0.6 mL), theresulting mixture was filtered and washed with THF, the filtrate wasconcentrated to give 444 mg of the title compound (86%). ¹H NMR (400MHz, CDCl₃): δ 1.67 (1H, t, J=6.0 Hz), 4.62 (2H, d, J=6.0 Hz), 5.10 2H,s), 6.87-6.91 (1H, m), 7.04-7.09 (4H, m), 7.40-7.43 (2H, m).

C.2-[5-[[4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 5.09 (2H, s), 5.16 (2H, s), 5.69 (1H, s), 6.98-7.13 (5H, m),7.37-7.40 (3H, m), 7.56 (1H, s), 8.03 (1H, s), 8.67 (1H, d, J=4.8 Hz).[M+H] Calc'd for C₂₃H₁₆F₂N₄O₂, 419. Found, 419.

D.2-[5-[[4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-fluoro-3-[(4-fluorophenyl)methoxy]phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 5.13 (2H, s), 5.23 (2H, s), 5.98 (1H, s), 7.07(1H, d, J=0.8 Hz), 7.18-7.25 (3H, m), 7.41 (1H, d, J=8.4 Hz), 7.48-7.51(2H, m), 7.57 (1H, s), 7.76 (1H, d, J=3.2 Hz), 8.06 (1H, s), 8.60 (1H,s).

Example 1402-[5-[[4-chloro-3-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-3-(cyclopropylmethoxy)phenyl]methanol

The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenoland bromocyclopropylmethanol according to the procedure for thepreparation of Example 111, part A. ¹H NMR (400 MHz, CDCl₃): δ 0.36-0.40(2H, m), 0.62-0.67 (2H, m), 1.29-1.33 (1H, m), 1.76 (1H, s), 3.89 (2H,d, J=6.8 Hz), 4.64 (2H, s), 6.84-6.86 (1H, m), 6.94 (1H, d, J=2.0 Hz),7.32 (1H, d, J=8.0 Hz).

B.2-[5-[[4-chloro-3-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-3-(cyclopropylmethoxy)phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.25-1.32 (1H, m), 3.88(2H, d, J=6.8 Hz), 5.18 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.92 (1H, dd,J=4.0 Hz, 8.0 Hz), 7.01 (1H, d, J=1.6 Hz), 7.37 (1H, d, J=8.0 Hz), 7.40(1H, dd, J=1.2 Hz, 5.2 Hz), 7.56 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.68(1H, d, J=5.2 Hz). [M+H] Calc'd for C₂₀H₁₇ClN₄O₂, 381. Found, 381.

C.2-[5-[[4-chloro-3-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-3-(cyclopropylmethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.30-0.34 (2H, m), 0.54-0.58 (2H, m),1.19-1.25 (1H, m), 3.87 (2H, d, J=6.4 Hz), 5.26 (2H, s), 6.01 (1H, d,J=1.6 Hz), 7.03 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.25 (1H, d, J=1.6 Hz), 7.41(1H, d, J=8.0 Hz), 7.59 (1H, d, J=2.0 Hz), 7.77 (1H, dd, J=1.6 Hz, 4.8Hz), 8.08 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd forC₂₀H₁₈ClN₃O₄, 400. Found, 400.

Example 1412-[5-[[4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. [4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanol

A mixture of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.34 g, 5.28mmol), 2-chloro-5-(hydroxymethyl)phenol (837 mg, 5.28 mmol), K₂CO₃ (1.46g, 10.56 mmol) and DMF (9 mL) was heated to 100° C. overnight. It wasthen poured into ice-water and extracted with ethyl acetate twice.Organic phase washed with water twice, brine and dried with Na₂SO₄,concentrated to a residue which was purified by flash columnchromatograph to give the title compound (903 mg, 75%). ¹H NMR (400 MHz,CDCl₃): δ 1.77 (1H, t, J=5.6 Hz), 4.42 (2H, q, J=8.0 Hz), 4.68 (2H, d,J=5.2 Hz), 6.99 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.02 (1H, s), 7.37 (1H, d,J=8.0 Hz).

B.2-[5-[[4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and[4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanol according to theprocedure for the preparation of Example 39, part C. ¹H NMR (400 MHz,CDCl₃): δ 4.41 (2H, d, J=7.6 Hz), 5.20 (2H, s), 5.73 (1H, d, J=2.0 Hz),7.08 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.14 (1H, d, J=2.0 Hz), 7.41-7.44 (2H,m), 7.57 (1H, d, J=1.6 Hz), 8.05 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H]Calc'd for C₁₈H₁₂ClF₃N₄O₂, 409. Found, 409.

C.2-[5-[[4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[[4-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 4.81-4.87 (2H, m), 5.26 (2H, s), 6.01 (1H, d,J=1.6 Hz), 7.17-7.20 (1H, m), 7.44 (1H, s), 7.50 (1H, d, J=8.0 Hz), 7.60(1H, d, J=2.0 Hz), 7.76 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.10 (1H, s), 8.68(1H, d, J=5.2 Hz). [M+H] Calc'd for C₁₈H₁₃ClF₃N₃O₄, 428. Found, 428.

Example 1422-[5-[(4-bromo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

2-[5-[(4-bromo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-bromo-3-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. [M+H] Calc'd for C₁₇H₁₃BrN₄O, 369.Found, 369.

B.2-[5-[(4-bromo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-bromo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.33 (3H, s), 5.24 (2H, s), 6.08 (1H, s),7.39-7.45 (3H, m), 7.61 (1H, s), 7.74 (1H, d, J=4.4 Hz), 8.06 (1H, s),8.66 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₄BrN₃O₃, 388. Found, 388.

Example 1432-[5-[(4-bromo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[5-[(4-bromo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-bromo-3-methoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 3.89 (3H,s), 5.20 (2H, s), 5.77 (1H, d, J=1.6 Hz), 7.06 (1H, d, J=1.2 Hz), 7.12(1H, dd, J=1.6 Hz, 8.0 Hz), 7.28 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.2Hz, 4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, t, J=0.8 Hz), 8.70 (1H,d, J=0.8 Hz, 4.8 Hz). [M+H] Calc'd for C₁₇H₁₃BrN₄O₂, 385. Found, 385.

B.2-[5-[(4-bromo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-bromo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.83 (3H, s), 5.18 (2H, s), 6.01 (1H, s), 7.17(1H, d, J=8.0 Hz), 7.24 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.59 (1H, s),7.74 (1H, d, J=4.8 Hz), 8.07 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H]Calc'd for C₁₇H₁₄1 N₃O₄, 404. Found, 404.

Example 1442-[5-[(4-iodo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-iodo-2-methylphenyl)methanol

The title compound was prepared from 4-iodo-2-methylbenzoic acidaccording to the procedure for the preparation of Example 123, part A.¹H NMR (400 MHz, CDCl₃): δ 2.29 (3H, s), 4.64 (2H, s), 7.09-7.11 (1H,m), 7.53-7.54 (2H, m).

B.2-[5-[(4-iodo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-iodo-2-methylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.33 (3H,s), 5.15 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.14 (1H, d, J=8.0 Hz), 7.39(1H, dd, J=1.6 Hz, 5.2 Hz), 7.55-7.59 (3H, m), 8.00 (1H, s), 8.66 (1H,d, J=5.2 Hz). [M+H] Calc'd for C₁₇H₁₃IN₄O, 417. Found, 417.

C.2-[5-[(4-iodo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-iodo-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 2.30 (3H, s), 5.22 (2H, s), 6.06 (1H, s), 7.28(1H, d, J=8.0 Hz), 7.56-7.61 (3H, m), 7.74 (1H, d, J=4.8 Hz), 8.05 (1H,s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₇H₁₄IN₃O₃, 436. Found,436.

Example 1452-[5-[(4-iodo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. (4-iodo-2-methoxyphenyl)methanol

A solution of methyl 4-iodo-2-methoxybenzoate (840 mg, 2.88 mmol) in THFwas purged with nitrogen and cooled to −78° C. DIBALH (6 mL, 5.75 mmol,1M in toluene) was added slowly. The mixture was then stirred at thesame temperature for an hour. Saturated aqueous NH₄Cl solution wasadded, followed by extraction with ethyl acetate twice. The organicphase was then washed with brine and dried with anhydrous Na₂SO₄.Solvent was removed and the resulting residue purified by flash columnchromatograph to give 237 mg of the title compound (31%). ¹H NMR (400MHz, CDCl₃): δ 2.17 (1H, s), 3.84 (3H, s), 4.62 (2H, d, J=4.0 Hz), 7.01(1H, d, J=7.6 Hz), 7.18 (1H, s), 7.29 (1H, d, J=8.0 Hz).

B.2-[5-[(4-iodo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-iodo-2-methoxyphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 3.88 (3H,s), 5.20 (2H, s), 5.77 (1H, d, J=2.0 Hz), 7.13 (1H, d, J=8.0 Hz), 7.23(1H, d, J=1.6 Hz), 7.33 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.39 (1H, dd, J=1.2Hz, 4.8 Hz), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, t, J=1.2 Hz), 8.70 (1H,d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C₁₇H₁₃1 N₄O₂, 433. Found, 433.

C.2-[5-[(4-iodo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-iodo-2-methoxyphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 3.82 (3H, s), 5.15 (2H, s), 5.93 (1H, d, J=1.6Hz), 7.25 (1H, d, J=8.0 Hz), 7.33-7.35 (2H, m), 7.52 (1H, d, J=2.0 Hz),7.67 (1H, d, J=4.8 Hz), 7.97 (1H, s), 8.50 (1H, d, J=4.8 Hz). [M+H]Calc'd for C₁₇H₁₄IN₃O₄, 451. Found, 451.

Example 1462-[5-[(5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 5-fluoro-2,3-dihydro-1H-inden-1-ol

Charged 5-fluoro-2,3-dihydroinden-1-one (486 mg, 3.22 mmol), methanol (8mL) and dichloromethane (4 mL) to a flask, the mixture was cooled to 0°C. and NaBH₄ (119 mg, 3.22 mmol) was added in portions. The reactionmixture was stirred at 0° C. for 15 min, warmed up to room temperatureand stirred for 30 min. Added water, extracted with ethyl acetate twice,and washed the organic phase with brine and dried with anhydrous Na₂SO₄,concentrated to give the title compound (488 mg, 100%). ¹H NMR (400 MHz,CDCl₃): δ 1.94-2.02 (1H, m), 2.46-2.55 (1H, m), 2.76-7.84 (1H, m),3.01-3.08 (1H, m), 5.20 (2H, t, J=5.6 Hz), 6.89-6.93 (2H, m), 7.32-7.36(1H, m).

B.2-[5-[(5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and5-fluoro-2,3-dihydro-1H-inden-1-ol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.39-2.46(1H, m), 2.59-2.64 (1H, m), 2.90-2.98 (1H, m), 3.13-3.20 (1H, m),5.72-5.75 (1H, m), 5.84 (1H, d, J=1.6 Hz), 6.89-6.94 (1H, m), 6.98 (1H,d, J=8.8 Hz), 7.34-7.37 (2H, m), 7.62 (1H, d, J=1.6 Hz), 7.86 (1H, s),8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₃FN₄O, 321. Found, 321.

C.2-[5-[(5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(5-fluoro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (800 MHz, CD₃OD-d₄): δ 2.38-2.45 (1H, m), 2.59-2.68 (1H, m),2.92-2.99 (1H, m), 3.16-3.24 (1H, m), 5.85-5.87 (1H, m), 6.12 (1H, d,J=3.2 Hz), 6.90-6.95 (1H, m), 7.02 (1H, dd, J=4.0 Hz, 18.4 Hz), 7.43(1H, dd, J=10.4 Hz, 17.6 Hz), 7.66 (1H, d, J=3.2 Hz), 7.81 (1H, dd,J=2.4 Hz, 9.6 Hz), 8.10 (1H, s), 8.61 (1H, d, J=9.6 Hz). [M+H] Calc'dfor C₁₅H₁₄FN₃O₃, 340. Found, 340.

Example 1472-[5-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 5-chloro-2,3-dihydro-1H-inden-1-ol

The title compound was prepared from 5-chloro-2,3-dihydroinden-1-oneaccording to the procedure for the preparation of Example 146, part A.

B.2-[5-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and5-chloro-2,3-dihydro-1H-inden-1-ol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 2.36-2.44(1H, m), 2.57-2.66 (1H, m), 2.90-2.98 (1H, m), 3.12-3.20 (1H, m),5.73-5.75 (1H, m), 5.85 (1H, d, J=2.0 Hz), 7.20 (1H, d, J=8.0 Hz), 7.29(1H, s), 7.32 (1H, d, J=8.0 Hz), 7.36 (1H, dd, J=1.8 Hz, 4.8 Hz), 7.63(1H, d, J=2.0 Hz), 7.87 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₅H₁₃ClN₄O, 337. Found, 337.

C.2-[5-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, CD₃OD-d₄): δ 2.35-2.43 (1H, m), 2.59-2.68 (1H, m),2.92-2.99 (1H, m), 3.14-3.22 (1H, m), 5.85-5.87 (1H, m), 6.13 (1H, d,J=1.6 Hz), 7.02 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.30 (1H, s), 7.39 (1H, d,J=8.0 Hz), 7.66 (1H, d, J=1.6 Hz), 7.81 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.11(1H, s), 8.61 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₈H₁₄ClN₃O₃, 356.Found, 356.

Example 1482-[5-[(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol

The title compound was prepared from6-fluoro-3,4-dihydro-2H-naphthalen-1-one according to the procedure forthe preparation of Example 146, part A. ¹H NMR (400 MHz, CDCl₃): δ1.69-2.01 (4H, m), 2.66-2.84 (2H, m), 4.85 (1H, t, J=4.4 Hz), 6.78 (1H,dd, J=2.4 Hz, 9.6 Hz), 6.86-6.91 (1H, m), 7.38 (1H, dd, J=6.0 Hz, 8.4Hz).

B.2-[5-[(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedurefor the preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ1.82-1.88 (1H, m), 1.99-2.10 (2H, m), 2.28-2.34 (1H, m), 2.74-2.94 (2H,m), 5.35 (1H, t, J=4.0 Hz), 5.85 (1H, d, J=1.6 Hz), 6.84-6.89 (2H, m),7.29 (1H, dd, J=5.6 Hz, 8.4 Hz), 7.36 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.63(1H, d, J=2.0 Hz), 7.86 (1H, s), 8.65 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₉H₁₅FN₄O, 335. Found, 335.

C.2-[5-[(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, CD₃OD-d₄): δ 1.71-1.76 (1H, m), 1.93-1.97 (2H, m),2.20-2.24 (1H, m), 2.63-2.77 (2H, m), 5.36-5.37 (1H, m), 6.01 (1H, d,J=1.6 Hz), 6.72-6.77 (2H, m), 7.19 (1H, dd, J=6.0 Hz, 8.4 Hz), 7.54 (1H,d, J=1.6 Hz), 7.69 (1H, d, J=4.8 Hz), 7.97 (1H, s), 8.49 (1H, d, J=4.8Hz). [M+H] Calc'd for C₁₉H₁₆FN₃O₃, 354. Found, 354.

Example 1492-[5-[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. 6-chloro-1,2,3,4-tetrahydronaphthalen-1-ol

The title compound was prepared from6-chloro-3,4-dihydro-2H-naphthalen-1-one according to the procedure forthe preparation of Example 146, part A. ¹H NMR (400 MHz, CDCl₃): δ 1.67(1H, d, J=5.6 Hz), 1.75-2.01 (3H, m), 2.67-2.82 (2H, m), 4.74 (1H, t,J=4.4 Hz), 7.09 (1H, s), 7.16 (1H, dd, J=2.4 Hz, 8.4 Hz), 7.36 (1H, d,J=8.0 Hz).

B.2-[5-[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and6-chloro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedurefor the preparation of Example 39, part C. [M+H] Calc'd for C₁₉H₁₅ClN₄O,351. Found, 351.

C.2-[5-[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(6-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, CD₃OD-d₄): δ 1.80-1.87 (1H, m), 2.02-2.11 (2H, m),2.26-2.32 (1H, m), 2.69-2.89 (2H, m), 5.43-5.45 (1H, m), 6.08 (1H, d,J=2.4 Hz), 7.12-7.13 (2H, m), 7.26-7.29 (1H, m), 7.62 (1H, d, J=2.0 Hz),7.76 (1H, dd, J=1.2 Hz, 5.2 Hz), 8.04 (1H, s), 8.50 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₉H₁₆ClN₃O₃, 370. Found, 370.

Example 1502-[5-[(2-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-bromo-2-chlorobenzoate

To a mixture of 4-bromo-2-chlorobenzoic acid (6.11 g, 25.94 mmol) inmethanol (60 mL) cooled to 0° C. was added SOCl₂ (6.17 g, 51.89 mmol)drop wise. The reaction mixture was stirred at 0° C. for 15 min then at70° C. for 3 h. It was then cooled to room temperature and removed thesolvent. The residue was purified by flash column chromatograph to give5.52 g of the title compound (85%). ¹H NMR (400 MHz, CDCl₃): δ 3.92 (3H,s), 7.45 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.63 (1H, d, J=2.0 Hz), 7.71 (1H,d, J=8.4 Hz).

B. methyl 2-chloro-4-ethenylbenzoate

The title compound was prepared from methyl 4-bromo-2-chlorobenzoate andvinyltrifluoroborate potassium salt according to the procedure for thepreparation of Example 135, part A. ¹H NMR (400 MHz, CDCl₃): δ 3.92 (3H,s), 5.41 (1H, d, J=11.2 Hz), 5.85 (1H, d, J=9.2 Hz), 6.66 (1H, dd,J=11.2 Hz, 17.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.47 (1H, s), 7.81 (1H, d,J=8.0 Hz).

C. methyl 2-chloro-4-ethylbenzoate

Charged methyl 2-chloro-4-ethenylbenzoate (437 mg, 2.23 mmol), BaSO₄/Pd(100 mg, 5%) and ethyl acetate (9 mL) to a flask, the mixture was thenpurged with H₂, and stirred at room temperature for 4 h. The reactionmixture was then filtered, concentrated to give 424 mg of the titlecompound (96%). ¹H NMR (400 MHz, CDCl₃): δ 1.24 (3H, t, J=7.6 Hz), 2.65(2H, q, J=7.6 Hz), 3.91 (3H, s), 7.12 (1H, dd, J=1.2 Hz, 8.4 Hz), 7.28(1H, d, J=1.6 Hz), 7.77 (1H, d, J=8.0 Hz).

D. (2-chloro-4-ethylphenyl)methanol

The title compound was prepared from methyl 2-chloro-4-ethylbenzoateaccording to the procedure for the preparation of Example 135, part C.The crude product was used for the next step without furtherpurification.

E.2-[5-[(2-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-chloro-4-ethylphenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.24 (3H,t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 5.30 (2H, s), 5.80 (1H, d, J=2.0Hz), 7.12-7.14 (1H, m), 7.26 (1H, s), 7.39 (1H, dd, J=1.6 Hz, 4.8 Hz),7.43 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.06 (1H, s), 8.71 (1H,d, J=4.4 Hz). [M+H] Calc'd for C₁₈H₁₅ClN₄O, 339. Found, 339.

F.2-[5-[(2-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.17 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6Hz), 5.29 (2H, s), 6.06 (1H, d, J=2.0 Hz), 7.22 (1H, d, J=2.0 Hz, 8.0Hz), 7.34 (1H, d, J=1.2 Hz), 7.58 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=2.0Hz), 7.75 (1H, dd, J=1.2 Hz, 4.8 Hz), 8.07 (1H, s), 8.67 (1H, d, J=5.2Hz). [M+H] Calc'd for C₁₈H₁₆ClN₃O₃, 358. Found, 358.

Example 1512-[5-[(4-ethyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-bromo-2-fluorobenzoate

The title compound was prepared from 4-bromo-2-fluorobenzoic acidaccording to the procedure for the preparation of Example 150, part A.The crude product was used for the next step without furtherpurification.

B. methyl 4-ethenyl-2-fluorobenzoate

The title compound was prepared from methyl 4-bromo-2-fluorobenzoate andvinyltrifluoroborate potassium salt according to the procedure for thepreparation of Example 135, part A. ¹H NMR (300 MHz, CDCl₃): δ 3.92 (3H,s), 5.43 (1H, d, J=11.1 Hz), 5.86 (1H, d, J=17.4 Hz), 6.69 (1H, dd,J=11.1 Hz, 17.4 Hz), 7.15 (1H, d, J=12.0 Hz), 7.21 (1H, dd, J=0.9 Hz,7.8 Hz), 7.89 (1H, t, J=8.1 Hz).

C. methyl 4-ethyl-2-fluorobenzoate

The title compound was prepared from methyl 4-ethenyl-2-fluorobenzoateaccording to the procedure for the preparation of Example 150, part C.¹H NMR (400 MHz, CDCl₃): 1.24 (3H, t, J=7.6 Hz), 2.68 (2H, q, J=7.6 Hz),3.91 (3H, s), 6.96 (1H, dd, J=11.6 Hz), 7.02 (1H, d, J=1.6 Hz, 8.0 Hz),7.82-7.86 (1H, m).

D. (4-ethyl-2-fluorophenyl)methanol

The title compound was prepared from methyl 4-ethyl-2-fluorobenzoateaccording to the procedure for the preparation of Example 135, part C.The crude product was used for the next step without furtherpurification.

E.2-[5-[(4-ethyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-ethyl-2-fluorophenyl)methanol according to the procedure for thepreparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ 1.23 (3H,t, J=7.6 Hz), 2.66 (2H, q, J=7.6 Hz), 5.26 (2H, s), 5.81 (1H, d, J=2.0Hz), 6.95 (1H, d, J=11.2 Hz), 7.00 (1H, d, J=7.6 Hz), 7.35 (1H, d, J=8.0Hz), 7.38 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.57 (1H, d, J=1.6 Hz), 8.00-8.01(1H, m), 8.69 (1H, d, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C₁₅H₁₅FN₄O,323. Found, 323.

F.2-[5-[(4-ethyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-ethyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 1.17 (3H, t, J=7.6 Hz), 2.61 (2H, q, J=7.6Hz), 5.27 (2H, s), 6.06 (1H, d, J=1.6 Hz), 7.06-7.10 (2H, m), 7.47-7.51(1H, m), 7.60 (1H, d, J=2.0 Hz), 7.74 (1H, dd, J=1.6 Hz, 5.2 Hz), 8.04(1H, d, J=0.8 Hz), 8.65-8.67 (1H, m). [M+H] Calc'd for C₁₈H₁₆FN₃O₃, 342.Found, 342.

Example 1522-[5-[(2-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 2-chloro-4-cyclopropylbenzoate

Charged methyl 4-bromo-2-chlorobenzoate (1.50 g, 6.01 mmol),cyclopropylboronic acid (931 mg, 10.82 mmol), Pd(PPh₃)₄ (347 mg, 0.30mmol), K₃PO₄ (1.82 g, 18.04 mmol), toluene (15 mL) and water (15 mL) toa flask, the mixture was then purged with nitrogen, and heated to 110°C. overnight. It was then cooled to room temperature and filtered, thefiltrate was extracted with ethylacetate twice, concentrated the organicphase and purified by flash column chromatograph to give 800 mg of thetitle compound (63%). ¹H NMR (400 MHz, CDCl₃): δ 0.73-0.77 (2H, m),0.98-1.07 (2H, m), 1.85-1.90 (1H, m), 3.90 (3H, s), 6.96 (1H, dd, J=1.6Hz, 8.0 Hz), 7.11 (1H, d, J=1.6 Hz), 7.74 (1H, d, J=8.0 Hz).

B. (2-chloro-4-cyclopropylphenyl)methanol

The title compound was prepared from methyl2-chloro-4-cyclopropylbenzoate according to the procedure for thepreparation of Example 135, part C. ¹H NMR (400 MHz, CDCl₃): δ 0.65-0.70(2H, m), 0.95-1.00 (2H, m), 1.83-1.90 (1H, m), 1.96 (1H, t, J=6.0 Hz),4.72 (2H, d, J=6.0 Hz), 6.97 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.06 (1H, d,J=1.6 Hz), 7.32 (1H, d, J=8.0 Hz).

C.2-[5-[(2-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(2-chloro-4-cyclopropylphenyl)methanol according to the procedure forthe preparation of Example 39, part C. [M+H] Calc'd for C₁₉H₁₅ClN₄O,351. Found, 351.

D.2-[5-[(2-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(2-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.69-0.73 (2H, m), 0.94-0.99 (2H, m),1.90-1.97 (1H, m), 5.26 (2H, s), 6.03 (1H, d, J=1.6 Hz), 7.07 (1H, d,J=8.4 Hz), 7.20 (1H, d, J=1.2 Hz), 7.52 (1H, d, J=7.6 Hz), 7.58 (1H, d,J=1.2 Hz), 7.73 (1H, d, J=4.8 Hz), 8.04 (1H, s), 8.61 (1H, d, J=5.2 Hz).[M+H] Calc'd for C₁₉H₁₆ClN₃O₃, 370. Found, 370.

Example 1532-[5-[(4-cyclopropyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-cyclopropyl-2-fluorobenzoate

The title compound was prepared from methyl 4-bromo-2-fluorobenzoate andcyclopropylboronic acid according to the procedure for the preparationof EXAMPLE 152, part A. ¹H NMR (400 MHz, CDCl₃): δ 0.74-0.78 (2H, m),1.04-1.09 (2H, m), 1.87-1.94 (1H, m), 3.90 (3H, s), 6.75-6.79 (1H, m),6.86-6.89 (1H, m), 7.79-7.82 (1H, m).

B. (4-cyclopropyl-2-fluorophenyl)methanol

The title compound was prepared from methyl4-cyclopropyl-2-fluorobenzoate according to the procedure for thepreparation of Example 135, part C. ¹H NMR (400 MHz, CDCl₃): δ 0.66-0.70(2H, m), 0.95-1.00 (2H, m), 1.77 (1H, t, J=6.0 Hz), 1.84-1.91 (1H, m),4.69 (2H, d, J=6.0 Hz), 6.71-6.75 (1H, m), 6.85-6.87 (1H, m), 7.24-7.28(1H, m).

C.2-[5-[(4-cyclopropyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-cyclopropyl-2-fluorophenyl)methanol according to the procedure forthe preparation of Example 39, part C. ¹H NMR (800 MHz, CDCl₃): δ0.68-0.73 (2H, m), 0.99-1.04 (2H, m), 1.86-1.92 (1H, m), 5.24 (2H, s),5.80 (1H, d, J=4.0 Hz), 6.78 (1H, dd, J=4.0 Hz, 23.2 Hz), 6.88 (1H, dd,J=3.2 Hz, 16.0 Hz), 7.30-7.34 (1H, m), 7.39 (1H, dd, J=1.6 Hz, 9.6 Hz),7.57 (1H, d, J=3.2 Hz), 8.00 (1H, s), 8.69 (1H, d, J=9.6 Hz). [M+H]Calc'd for C₁₉H₁₅FN₄O, 335. Found, 335.

D.2-[5-[(4-cyclopropyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-cyclopropyl-2-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.69-0.73 (2H, m), 0.95-0.99 (2H, m),1.90-1.97 (1H, m), 5.24 (2H, s), 6.05 (1H, d, J=2.0 Hz), 6.91-6.96 (2H,m), 7.42-7.46 (1H, m), 7.59 (1H, d, J=2.0 Hz), 7.73 (1H, dd, J=1.6 Hz,4.8 Hz), 8.03 (1H, s), 8.64-8.65 (1H, m). [M+H] Calc'd for C₁₉H₁₆FN₃O₃,354. Found, 354.

Example 1542-[5-[(3-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 3-chloro-4-cyclopropylbenzoate

The title compound was prepared from methyl 4-bromo-3-chlorobenzoate andcyclopropylboronic acid according to the procedure for the preparationof EXAMPLE 152, part A. ¹H NMR (400 MHz, CDCl₃): δ 0.73-0.77 (2H, m),1.07-1.12 (2H, m), 2.24-2.30 (1H, m), 3.90 (3H, s), 6.93 (1H, d, J=8.0Hz), 7.80 (1H, dd, J=1.6 Hz, 8.0 Hz), 8.01 (1H, d, J=1.6 Hz).

B. (3-chloro-4-cyclopropylphenyl)methanol

The title compound was prepared from methyl3-chloro-4-cyclopropylbenzoate according to the procedure for thepreparation of Example 135, part C. The crude product was used for nextstep without further purifications.

C.2-[5-[(3-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(3-chloro-4-cyclopropylphenyl)methanol according to the procedure forthe preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ0.68-0.71 (2H, m), 1.01-1.06 (2H, m), 2.16-2.23 (1H, m), 5.17 (2H, s),5.73 (1H, d, J=2.0 Hz), 6.94 (1H, d, J=8.0 Hz), 7.20 (1H, dd, J=1.6 Hz,8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.45 (1H, d, J=1.6 Hz), 7.56(1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'dfor C₁₉H₁₅ClN₄O, 351. Found, 351.

D.2-[5-[(3-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(3-chloro-4-cyclopropylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.66-0.75 (2H, m), 0.95-1.07 (2H, m),2.09-2.16 (1H, m), 5.24 (2H, s), 6.00 (1H, s), 7.03 (1H, d, J=8.4 Hz),7.33 (1H, d, J=8.4 Hz), 7.57 (2H, d, J=17.6 Hz), 7.76 (1H, d, J=4.0 Hz),8.07 (1H, s), 8.68 (1H, d, J=4.8 Hz). [M+H] Calc'd for C₁₉H₁₆ClN₃O₃,370. Found, 370.

Example 1552-[5-[(4-cyclopropyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-cyclopropyl-3-fluorobenzoate

The title compound was prepared from methyl 4-bromo-3-fluorobenzoate andcyclopropylboronic acid according to the procedure for the preparationof EXAMPLE 152, part A. ¹H NMR (400 MHz, CDCl₃): δ 0.77-0.81 (2H, m),1.04-1.09 (2H, m), 2.12-2.16 (1H, m), 3.89 (3H, s), 6.88-6.92 (1H, m),7.63-7.66 (1H, m), 7.69-7.72 (1H, m).

B. (4-cyclopropyl-3-fluorophenyl)methanol

The title compound was prepared from methyl4-cyclopropyl-3-fluorobenzoate according to the procedure for thepreparation of Example 135, part C. The crude product was used for nextstep without further purifications.

C.2-[5-[(4-cyclopropyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and(4-cyclopropyl-3-fluorophenyl)methanol according to the procedure forthe preparation of Example 39, part C. ¹H NMR (400 MHz, CDCl₃): δ0.71-0.75 (2H, m), 0.96-1.02 (2H, m), 2.06-2.10 (1H, m), 5.17 (2H, s),5.72 (1H, d, J=1.6 Hz), 6.88-6.92 (1H, m), 7.07-7.10 (2H, m), 7.40 (1H,dd, J=1.6 Hz, 5.2 Hz), 7.55 (1H, d, J=2.0 Hz), 8.02 (1H, s), 8.70 (1H,d, J=5.2 Hz). [M+H] Calc'd for C₁₉H₁₅FN₄O, 335. Found, 335.

D.2-[5-[(4-cyclopropyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[5-[(4-cyclopropyl-3-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 28, part E. ¹HNMR (400 MHz, DMSO-d₆): δ 0.69-0.73 (2H, m), 0.94-0.99 (2H, m),1.98-2.04 (1H, m), 5.24 (2H, s), 5.99 (1H, d, J=1.6 Hz), 6.98-7.01 (1H,m), 7.20 (1H, d, J=8.0 Hz), 7.24 (1H, dd, J=1.6 Hz, 11.6 Hz), 7.58 (1H,d, J=2.0 Hz), 7.76 (1H, dd, J=1.6 Hz, 4.8 Hz), 8.07 (1H, s), 8.68 (1H,dd, J=0.4 Hz, 4.8 Hz). [M+H] Calc'd for C₁₉H₁₆FN₃O₃, 354. Found, 354.

Example 1562-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylicacid A.2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-1-yl]pyridine-4-carbonitrile

A mixture of 2-chloropyridine-4-carbonitrile (1.38 g, 10 mmol),tert-butyl-dimethyl-[2-(1H-pyrazol-4-yl)ethoxy]silane (2.481 g, 11 mmol)in NMP (30 mL) was stirred for 5 hr at 150° C. Then the reaction mixturewas cooled to room temperature and poured into water and extracted withethyl acetate three times. Organic extracts collected and washed withwater twice, brine and dried with anhydrous Na₂SO₄. It was thenconcentrated and purified by flash column chromatograph to give thetitle compound (1.2 g, 36%). [M+H] Calc'd for C₁₇H₂₄N₄O₃Si, 329. Found,329.

B. 2-[4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile

To a solution of2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazol-1-yl]pyridine-4-carbonitrile(1.2 g, 3.6 mmol) in THF (15 mL) at 0° C. was added 3N HCl (5 mL). Thereaction mixture was then stirred for 2 hours at room temperature. Coolto 0° C., added ethyl acetate, water and acidified with NaHCO₃ to pH=8.The mixture was then extracted with ethylacetate, concentrated to affordthe title compound (700 mg, 91%). [M+H] Calc'd for C₁₁H₁₀N₄O, 215.Found, 215.

C. 2-[1-(4-cyanopyridin-2-yl)pyrazol-4-yl]ethyl methanesulfonate

To a mixture of2-[4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile (700 mg, 3.3mmol), Et₃N (670 mg, 6.6 mmol) in DCM (15 mL) was added MeSO₂Cl (410 mg,3.6 mmoL) at 0° C., the mixture was then stirred for 2 hours at roomtemperature, water was added and extracted with DCM and concentratedgive the title compound (830 mg, 87%). [M+H] Calc'd for C₁₂H₁₂N₄O₃S,293. Found, 293.

D.2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carbonitrile

To a mixture of 2-[1-(4-cyanopyridin-2-yl)pyrazol-4-yl]ethylmethanesulfonate (476 mg, 1.6 mmol) and (4-flouro-benzyl)-methyl-amine(444 mg, 3.2 mmol) in ACN (30 mL) at rt was added K₂CO₃ (4.5 g, 32 mmol)and KI (1.0 g, 6.2 mmol. The reaction mixture was heated to 80° C. andstirred overnight. Filtered, solvent removed and purified by prep-HPLCto give the title compound (270 mg, 50%). [M+H] Calc'd for C₁₉H₁₈FN₅,336. Found, 336.

E.2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylicacid

Charged2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carbonitrile(270 mg, 0.8 mmol), NaOH aqueous (5M, 0.5 mL) and ethanol (10 mL) to aflask, the mixture was then heated to reflux for half an hour, cooled inan ice-water bath, adjusted PH to 3-4, filtered, collected the solid anddried to give the title compound (226 mg, 80%). ¹H NMR (400 MHz,DMSO-d6): 2.70 (3H, s), 3.01-3.06 (2H, m), 3.25-3.27 (1H, m), 3.31-3.39(1H, m), 4.26-4.30 (1H, m), 4.44-4.48 (1H, m), 7.29-7.34 (2H, m),7.64-7.68 (2H, m), 7.74-7.76 (1H, m), 7.81 (1H, s), 8.28 (1H, s), 8.61(s, 1H), 8.64 (1H, J=5.2 Hz, d), 10.49 (1H, br). [M+H] Calc'd forC₁₉H₁₉FN₄O₂, 355. Found, 355.

Example 157N-cyano-2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxamide

A mixture of2-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylicacid (70 mg, 0.2 mmol), cyanamide (17 mg, 0.4 mmol), HATU (113 mg, 0.3mmol) and DIEA (59 mg, 0.6 mmol) in DMF (3 mL) was stirred at roomtemperature for 3 hours. The mixture was concentrated and purifiedbyprep-HPLC to give the compound (15 mg, 20%). ¹H NMR (400 MHz,DMSO-d6): 2.67-2.74 (3H, m), 2.94-2.98 (2H, m), 3.28 (1H, m), 3.43-3.45(1H, m), 4.26-4.30 (1H, m), 4.44-4.48 (1H, m), 7.31-7.36 (2H, m),7.59-7.61 (2H, m), 7.70-7.71 (1H, m), 7.76 (1H, s), 8.31 (1H, s), 8.42(1H, d, J=5.2 Hz), 8.58 (1H, s), 9.56 (1H, br). [M+H] Calc'd forC₂₀H₁₉FN₆O, 379. Found, 379.

Example 1582-[3-(4-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acidA. 2-[3-(4-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

To a mixture of ethyl 3-(4-chlorophenyl)-3-oxopropanoate (500 mg, 2.2mmol) and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2, 296 mg,2.2 mmol) in EtOH (15 mL) was added AcOH (2 mL) at r.t. The reactionmixture was stirred at 90° C. overnight. After the reaction wascompleted, the mixture was concentrated, washed with PE/EA (10 mL,V/V=1/1) to give the title compound (500 mg, 76%) as a brown solid andused as crude for next step.

B. 2-[3-(4-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

To a solution of2-[3-(4-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile (250mg, 0.85 mmol) in EtOH (10 mL) and water (5 mL) was added NaOH (168 mg,4.2 mmol) at r.t. The reaction mixture was stirred at 90° C. for 2 h.Removed EtOH, acidified with 1N HCl to pH 5, filtered, washed with ethylacetate (5 mL) to give the title compound (200 mg, 75%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.20 (1H, s), 7.50 (2H, d, J=8.4Hz), 7.76 (1H, d, J=4.0 Hz), 7.91 (2H, d, J=8.4 Hz), 8.26 (1H, s), 8.65(1H, d, J=5.2 Hz), 12.20 (1H, brs), 13.96 (1H, brs). [M+H] Calc'd forC₁₅H₁₀ClN₃O₃, 316. Found, 316.

Example 1592-[3-(3-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acidA. 2-[3-(3-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 53% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-(3-chlorophenyl)-3-oxopropanoate according to the procedure for thepreparation of Example 158, part A.

B. 2-[3-(3-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 75% yield from2-[3-(3-chlorophenyl)-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, DMSO-d₆): δ 6.18 (1H, s), 7.40-7.49 (2H, m), 7.73 (1H,d, J=4.2 Hz), 7.83-7.90 (2H, m), 8.33 (1H, s), 8.57 (1H, d, J=4.8 Hz).[M+H] Calc'd for C₁₅H₁₀ClN₃O₃, 316. Found, 316.

Example 160 2-(3-cyclopentyl-5-hydroxypyrazol-1-yl)pyridine-4-carboxylicacid A. 2-(3-cyclopentyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile

The title compound was prepared in 72% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-cyclopentyl-3-oxopropanoate according to the procedure for thepreparation of Example 158, part A.

B. 2-(3-cyclopentyl-5-hydroxypyrazol-1-yl)pyridine-4-carboxylic acid

The title compound was prepared in 75% yield from2-(3-cyclopentyl-5-hydroxypyrazol-1-yl)pyridine-4-carbonitrile accordingto the procedure for the preparation of Example 158, part B. ¹H NMR (400MHz, CD₃OD): δ 1.71-1.85 (6H, m), 2.11-2.14 (2H, m), 3.04-3.08 (1H, m),7.73 (1H, dd, J=0.8, 5.2 Hz), 8.57 (1H, d, J=5.2 Hz), 8.82 (1H, s).[M+H] Calc'd for C₁₄H₁₅N₃O₃, 274. Found, 274.

Example 1612-[3-[(2,6-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(2,6-difluorophenyl)-3-oxobutanoate

The title compound was prepared from 2-(2,6-difluorophenyl)acetic acidand 3-methoxy-3-oxopropanoic acid potassium salt according to theprocedure for the preparation of Example 170, part A. ¹H NMR (300 MHz,CDCl₃): δ 3.56 (2H, s), 3.75 (3H, s), 3.92 (2H, s), 6.89-6.93 (2H, m),7.22-7.27 (1H, m).

B.2-[3-[(2,6-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(2,6-difluorophenyl)-3-oxobutanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[(2,6-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 26% yield from2-[3-[(2,6-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD/DMSO-d₆): δ 3.92 (2H, s), 7.03-7.08 (2H, m),7.32-7.37 (1H, m), 7.65-7.67 (1H, m), 8.54 (1H, d, J=5.1 Hz). [M+H]Calc'd for C₁₆H₁₁F₂N₃O₃, 332. Found, 332.

Example 1622-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carboxylic acid A.ethyl 3-oxo-4-phenylpentanoate

To a solution of 2-phenylpropanoic acid g, 33.3 mmol) in DCM (50 mL) wasadded (COCl)₂ (8.5 g, 66.7 mmol) and 2 drops of DMF in ice-bath. Thereaction mixture was stirred at r.t. for 2 h. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure.To a solution of pyridine (6 mL) in DCM (50 mL) was added2,2-dimethyl-1,3-dioxane-4,6-dione (5.8 g, 40.0 mmol) and the aboveresidue in ice-bath. The reaction mixture was stirred at r.t. for 2 h.Diluted with 1N HCl (50 mL), extracted with DCM (50 mL×3), washed withbrine (50 mL), dried over Na₂SO₄, filtered, concentrated to give aresidue. The residue was dissolved in EtOH (50 mL) and then stirred atreflux for 3 h. Removed solvent, purified by flash column chromatographyto give the title compound (3.6 g, 49%) as a yellow oil. ¹H NMR (400MHz, CDCl₃): δ 1.22 (3H, t, J=7.2 Hz), 1.41 (3H, d, J=7.2 Hz), 3.28 (1H,d, J=15.6 Hz), 3.40 (1H, d, J=15.6 Hz), 3.89-3.91 (1H, m), 4.11-4.14(2H, m), 7.20-7.22 (2H, m), 7.27-7.36 (3H, m).

B. 2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 40% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl3-oxo-4-phenylpentanoate according to the procedure for the preparationof Example 158, part A.

C. 2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carboxylic acid

The title compound was prepared in 40% yield from2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD): δ 1.65 (3H, d, J=7.2 Hz), 4.09-4.16 (1H, m),7.23-7.25 (1H, m), 7.29-7.36 (4H, m), 7.72 (1H, dd, J=1.2, 5.1 Hz), 8.53(1H, d, J=5.4 Hz), 8.70 (1H, s). [M+H] Calc'd for C₁₇H₁₅N₃O₃, 310.Found, 310.

Example 1632-[3-[(2-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. ethyl 4-(2-chlorophenyl)-3-oxobutanoate

The title compound was prepared in 43% yield from2-(2-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dioneaccording to the procedure for the preparation of Example 162, part A.

B.2-[3-[(2-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 39% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl4-(2-chlorophenyl)-3-oxobutanoate according to the procedure for thepreparation of Example 158, part A.

C.2-[3-[(2-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 57% yield from2-[3-[(2-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD): δ 4.07 (2H, s), 7.25-7.29 (2H, m), 7.37-7.43(2H, m), 7.72 (1H, dd, J=0.9, 3.9 Hz), 8.52 (1H, d, J=4.2 Hz), 8.65 (1H,brs). [M+H] Calc'd for C₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 1642-[3-[(3-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. ethyl 4-(3-chlorophenyl)-3-oxobutanoate

The title compound was prepared in 43% yield from2-(3-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dioneaccording to the procedure for the preparation of Example 162, part A.

B.2-[3-[(3-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 32% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl4-(3-chlorophenyl)-3-oxobutanoate according to the procedure for thepreparation of Example 158, part A.

C.2-[3-[(3-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 47% yield from2-[3-[(3-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (400 MHz, CD₃OD): δ 3.92 (2H, s), 7.25-7.34 (4H, m), 7.73 (1H,dd, J=5.2 Hz), 8.53 (1H, d, J=5.2 Hz), 8.66 (1H, brs). [M+H] Calc'd forC₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 1652-[3-[(4-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. ethyl 4-(4-chlorophenyl)-3-oxobutanoate

The title compound was prepared in 43% yield from2-(4-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dioneaccording to the procedure for the preparation of Example 162, part A.

B.2-[3-[(4-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared in 32% yield from2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl4-(4-chlorophenyl)-3-oxobutanoate according to the procedure for thepreparation of Example 158, part A.

C.2-[3-[(4-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 61% yield from2-[3-[(4-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (400 MHz, CD₃OD): δ 3.91 (2H, s), 7.29-7.31 (4H, m), 7.72 (1H,dd, J=1.2, 5.2 Hz), 8.51 (1H, d, J=5.2 Hz), 8.63 (1H, brs). [M+H] Calc'dfor C₁₆H₁₂ClN₃O₃, 330. Found, 330.

Example 1665-(1-phenylethyl)-2-[4-(1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol

To a suspension of2-[5-hydroxy-3-(1-phenylethyl)pyrazol-1-yl]pyridine-4-carbonitrile (150mg, 0.5 mmol), NH₄Cl (278 mg, 5.2 mmol) in DMF (5 mL) was added NaN₃(338 mg, 5.2 mmol) at r.t. The reaction mixture was stirred at 110° C.for 2 h in a microwave oven. The reaction mixture was then filtered andpurified by pre-HPLC to give the title compound (100 mg, 58%) as a brownsolid. ¹H NMR (400 MHz, CD₃OD): δ 1.64 (3H, d, J=7.2 Hz), 4.07-4.12 (1H,m), 7.17-7.19 (1H, m), 7.20-7.35 (4H, m), 7.83 (1H, dd, J=1.2, 5.2 Hz),8.43 (1H, d, J=5.2 Hz), 8.74 (1H, s). [M+H] Calc'd for C₁₇H₁₅N₇O, 334.Found, 334.

Example 1675-[(2-chlorophenyl)methyl]-2-[4-(1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol

The title compound was prepared in 47% yield from2-[3-[(2-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 166. ¹H NMR(400 MHz, CD₃OD): δ 4.06 (2H, s), 7.23-7.28 (2H, m), 7.37-7.41 (2H, m),7.85 (1H, dd, J=1.2, 5.2 Hz), 8.44 (1H, d, J=5.2 Hz), 8.70 (1H, s).[M+H] Calc'd for C₁₆H₁₂ClN₇O, 354. Found, 354.

Example 1685-[(3-chlorophenyl)methyl]-2-[4-(1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol

The title compound was prepared in 43% yield from2-[3-[(3-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 166. ¹H NMR(400 MHz, CD₃OD): δ 3.91 (2H, s), 7.21-7.33 (4H, m), 7.85 (1H, dd,J=1.6, 5.6 Hz), 8.47 (1H, d, J=5.2 Hz), 8.72 (1H, s). [M+H] Calc'd forC₁₆H₁₂ClN₇O, 354. Found, 354.

Example 1695-[(4-chlorophenyl)methyl]-2-[4-(1H-tetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol

The title compound was prepared in 47% yield from2-[3-[(4-chlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 166. ¹H NMR(400 MHz, CD₃OD): δ 3.97 (2H, s), 7.35 (4H, s), 7.91 (1H, dd, J=1.2, 5.2Hz), 8.62 (1H, d, J=5.2 Hz), 8.85 (1H, s). [M+H] Calc'd for C₁₆H₁₂ClN₇O,354. Found, 354.

Example 1702-[3-[2-(4-chlorophenyl)propan-2-yl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(4-chlorophenyl)-4-methyl-3-oxopentanoate

To a solution of 2-(4-chlorophenyl)-2-methylpropanoic acid (200 mg, 1.01mmol) in THF (20 mL) was added CDI (172 mg, 1.06 mmol) at rt. Thereaction mixture was stirred at rt for 2 h. Added MgCl₂ (105 mg, 1.11mmol) and 3-methoxy-3-oxopropanoic acid potassium salt (173 mg, 1.11mmol) at rt. The mixture was stirred at 60° C. overnight. Dilute withethyl acetate (100 mL), washed with 0.5 N HCl (20 mL×2) and brine (50mL), dried over Na₂SO₄, filtered, concentrated, purified by flash columnchromatography to give the title compound (60 mg, 23%) as a yellow oil.¹H NMR (300 MHz, CDCl₃): δ 1.51 (6H, s), 3.28 (2H, s), 3.67 (3H, s),7.20-7.30 (2H, m), 7.34-7.37 (2H, m).

B.2-[3-[2-(4-chlorophenyl)propan-2-yl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(4-chlorophenyl)-4-methyl-3-oxopentanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[2-(4-chlorophenyl)propan-2-yl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 40% yield from2-[3-[2-(4-chlorophenyl)propan-2-yl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD/DMSO-d₆): δ 1.58 (6H, s), 7.27-7.35 (4H, m),7.66-7.69 (1H, m), 8.18-8.19 (1H, m), 8.53 (1H, dd, J=0.6, 5.1 Hz).[M+H] Calc'd for C₁₈H₁₆ClN₃O₃, 358. Found, 358.

Example 1712-[3-[1-(4-chlorophenyl)cyclopropyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 3-[1-(4-chlorophenyl)cyclopropyl]-3-oxopropanoate

The title compound was prepared in 78% yield from1-(4-chlorophenyl)cyclopropane-1-carboxylic acid and3-methoxy-3-oxopropanoic acid potassium salt according to the procedurefor the preparation of Example 170, part A. ¹H NMR (300 MHz, CDCl₃): δ1.22-1.26 (2H, m), 1.70-1.74 (2H, m), 3.35 (2H, s), 3.67 (3H, s),7.29-7.34 (4H, m).

B.2-[3-[1-(4-chlorophenyl)cyclopropyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl3-[1-(4-chlorophenyl)cyclopropyl]-3-oxopropanoate according to theprocedure for the preparation of Example 158, part A.

C.2-[3-[1-(4-chlorophenyl)cyclopropyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 36% yield from2-[3-[1-(4-chlorophenyl)cyclopropyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD/DMSO-d₆): δ 1.19-1.21 (2H, m), 1.40-1.42 (2H, m),7.29-7.36 (4H, m), 7.64-7.65 (1H, m), 8.15 (1H, brs), 8.50 (1H, d, J=5.4Hz). [M+H] Calc'd for C₁₈H₁₄ClN₃O₃, 356. Found, 356.

Example 1722-[3-[(3,5-dichlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(3,5-dichlorophenyl)-3-oxobutanoate

The title compound was prepared in 78% yield from2-(3,5-dichlorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acidpotassium salt according to the procedure for the preparation of Example170, part A.

B.2-[3-[(3,5-dichlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(3,5-dichlorophenyl)-3-oxobutanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[(3,5-dichlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 59% yield from2-[3-[(3,5-dichlorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD/DMSO-d₆): δ 4.06 (2H, m), 7.52-7.54 (3H, m),7.83-7.84 (1H, m), 8.72 (1H, d, J=5.1 Hz). [M+H] Calc'd forC₁₆H₁₁Cl₂N₃O₃, 364. Found, 364.

Example 1732-[3-[(4-fluoro-2-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(4-fluoro-2-methylphenyl)-3-oxobutanoate

The title compound was prepared in 78% yield from2-(4-fluoro-2-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acidpotassium salt according to the procedure for the preparation of Example170, part A. ¹H NMR (300 MHz, CDCl₃): δ 2.24 (3H, s), 3.47 (2H, s), 3.74(3H, s), 3.83 (2H, s), 6.88-6.94 (2H, m), 7.07-7.12 (1H, m).

B.2-[3-[(4-fluoro-2-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(4-fluoro-2-methylphenyl)-3-oxobutanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[(4-fluoro-2-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 41% yield from2-[3-[(4-fluoro-2-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD): δ 2.34 (3H, s), 3.92 (2H, s), 6.87-6.98 (2H,m), 7.23-7.28 (1H, m), 7.75 (1H, dd, J=1.2, 5.1 Hz), 8.55 (1H, d, J=5.1Hz), 8.72 (1H, brs). [M+H] Calc'd for C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 1742-[3-[(2-fluoro-4-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(2-fluoro-4-methylphenyl)-3-oxobutanoate

The title compound was prepared from 2-(2-fluoro-4-methylphenyl)aceticacid and 3-methoxy-3-oxopropanoic acid potassium salt according to theprocedure for the preparation of Example 170, part A. ¹H NMR (300 MHz,CDCl₃): δ 2.35 (3H, s), 3.52 (2H, s), 3.74 (3H, s), 3.83 (2H, s),6.89-6.95 (2H, m), 7.05-7.08 (1H, m).

B.2-[3-[(2-fluoro-4-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonit

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(2-fluoro-4-methylphenyl)-3-oxobutanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[(2-fluoro-4-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared from2-[3-[(2-fluoro-4-methylphenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD): δ 2.33 (3H, s), 3.92 (2H, s), 6.92-6.97 (2H,m), 7.18-7.24 (1H, m), 7.73 (1H, d, J=4.8 Hz), 8.54 (1H, d, J=4.8 Hz),8.69 (1H, brs). [M+H] Calc'd for C₁₇H₁₄FN₃O₃, 328. Found, 328.

Example 1752-[3-[(2,4-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid A. methyl 4-(2,4-difluorophenyl)-3-oxobutanoate

The title compound was prepared from 2-(2,4-difluorophenyl)acetic acidand 3-methoxy-3-oxopropanoic acid potassium salt according to theprocedure for the preparation of Example 170, part A. ¹H NMR (300 MHz,CDCl₃): δ 3.54 (2H, s), 3.76 (3H, s), 3.86 (2H, s), 6.83-6.90 (2H, m),7.13-7.19 (1H, m).

B.2-[3-[(2,4-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile

The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile(PREPARATION 2) and methyl 4-(2,4-difluorophenyl)-3-oxobutanoateaccording to the procedure for the preparation of Example 158, part A.

C.2-[3-[(2,4-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carboxylicacid

The title compound was prepared in 20% yield from2-[3-[(2,4-difluorophenyl)methyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrileaccording to the procedure for the preparation of Example 158, part B.¹H NMR (300 MHz, CD₃OD/DMSO-d₆): δ 3.88 (2H, s), 6.97-7.04 (1H, m),7.11-7.17 (1H, m), 7.37-7.43 (1H, m), 7.65-7.66 (1H, m), 8.56 (1H, d,J=5.1 Hz). [M+H] Calc'd for C₁₆H₁₁F₂N₃O₃, 332. Found, 332.

II. Biological Evaluation Example 1 In Vitro Enzyme Inhibition Assay

This assay determines the ability of a test compound to inhibit JaridlA,Jarid1B, JMJD2C, and JMJD2A demethylase activity. Baculovirus expressedJaridlA (GenBank Accession #NM_001042603, AA1-1090) was purchased fromBPS Bioscience (Cat#50110). Baculovirus expressed Jarid1B (GenBankAccession #NM_006618, AA 2-751) was purchased from BPS Bioscience (Cat#50121) or custom made by MolecularThroughput. Baculovirus expressedJMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPSBioscience (Cat#50105). Baculovirus expressed JMJD2A (GenBank Accession#NM_014663, AA 1-350) was purchased from BPS Bioscience (Cat#50123).Baculovirus expressed FBXL10 (GenBank Accession #NM_032590, AA 1-650)was purchased from BPS Bioscience (Cat#50120).

Jarid1A Assay

The enzymatic assay of JaridlA activity is based upon TimeResolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. Theability of test compounds to inhibit the activity of JaridlA wasdetermined in 384-well plate format under the following reactionconditions: 1 nM JaridlA, 300 nM H3K4me3-biotin labeled peptide (Anaspeccat #64357), 2 alpha-ketoglutaric acid in assay buffer of 50 mM HEPES,pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono- or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of plate, followed by the addition of 2 μl of 3 nM JaridlAto initiate the reaction. The reaction mixture was incubated at roomtemperature for 30 minutes, and terminated by the addition of 6 μl of 5mM EDTA in LANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me1-2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

Jarid1B Assay

The ability of test compounds to inhibit the activity of Jarid1B wasdetermined in 384-well plate format under the following reactionconditions: 0.8 nM Jarid1B, 300 nM H3K4me3-biotin labeled peptide(Anaspec cat #64357), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-mono- or di-methylated histone H3 lysine 4 (H3K4me1-2)antibody (PerkinElmer) in the presence of 5 mM EDTA in LANCE detectionbuffer (PerkinElmer) at a final concentration of 25 nM and 1 nM,respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of the plate, followed by the addition of 2 μl of 2.4 nMJarid1B to initiate the reaction. The reaction mixture was incubated atroom temperature for 30 minutes, and terminated by the addition of 6 μlof 5 mM EDTA in LANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me1-2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 0.9nM JMJD2C to initiate the reaction. The reaction mixture was incubatedat room temperature for 30 minutes, and terminated by the addition of 6μl of 5 mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC₅₀).

JMJD2A Assay

The ability of test compounds to inhibit the activity of JMJD2A wasdetermined in 384-well plate format under the following reactionconditions: 2 nM JMJD2A, 300 nM H3K9me3-biotin labeled peptide (Anaspeccat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50 mMHEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of plate, followed by the addition of 2 μl of 6 nMJMJD2A to initiate the reaction. The reaction mixture was incubated atroom temperature for 30 minutes, and terminated by the addition of 6 μlof 5 mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hourincubation at room temperature. A ratio was calculated (665/615) foreach well and fitted to determine inhibition constant (IC50).

FBXL10 Assay

The ability of test compounds to inhibit the activity of FBXL10 wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM FBXL10, 30 nM H3K36me2-biotin labeled peptide(Anaspec cat #64442), 0.2 μM alpha-ketoglutaric acid in assay buffer of50 mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μMsodium L-ascorbate, and 5 μM ammonium iron(II) sulfate. Reaction productwas determined quantitatively by AlphaScreen detection after theaddition of detection reagents anti-H3K36me1 antibody, AlphaScreen®Streptavidin-coated Donor beads, and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA to final 10 μg/ml beads.

The assay reaction was initiated by the following: 3 μl of the mixtureof 90 nM H3K36me2-biotin labeled peptide and 0.6 μM alpha-ketoglutaricacid with 3 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of 384 well Proxiplate (Perkin Elmer), followed bythe addition of 3 μl of 0.9 nM FBXL10 to initiate the reaction. Thereaction mixture was incubated at room temperature for 30 minutes, andterminated by the addition of 3 μl of 50 mM HEPES, pH7.3, 10 mM NaCl,0.005% Brij35, 5 mM EDTA, 2 mg/ml BSA containing appropriate dilution ofanti H3K36me1 antibody. Plates were incubated at room temperature for 40minutes, followed by addition of 3 μl of 50 μg/ml AlphaScreen®Streptavidin-coated Donor beads and AlphaScreen® Protein A Acceptorbeads in 50 mM HEPES, pH7.3, 10 mM NaCl, 0.005% Brij35, 5 mM EDTA, 2mg/ml BSA. Plates were read by EnVisionMultilabel Reader in AlphaScreenmode after a minimum of 2 hour or up to overnight incubation at roomtemperature. The AlphaScreen signal for each well was used to determineinhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Tables 3 provides the IC₅₀ values of various compounds disclosed herein.

TABLE 3 Chemical Synthesis JARID1A JARID1B JMJD2C JMJD2A FBXL10 ExampleName IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) 12-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)iso- B A B B nicotinic acid 22-(3-cyclopropyl-5-hydroxy-1H-pyrazol-1-yl)iso- A A B B A nicotinic acid3 2-(5-hydroxy-3,4-dimethyl-1H-pyrazol-1-yl)iso- B A B B nicotinic acid4 2-(5-hydroxy-3-methyl-4-phenyl-1H-pyrazol-1- C C C B yl)isonicotinicacid 5 2-(3-(2-fluorophenyl)-5-hydroxy-1H-pyrazol-1- C C C Ayl)isonicotinic acid 6 2-(5-hydroxy-3-propyl-1H-pyrazol-1-yl)iso- B B BB nicotinic acid 7 2-(3-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-1- C C D Ayl)isonicotinic acid 8 2-(3-benzyl-5-hydroxy-1H-pyrazol-1-yl)iso- B B CA nicotinic acid 9 2-(5-hydroxy-3-(methoxymethyl)-1H-pyrazol-1- B B C Ayl)isonicotinic acid 10 2-(5-hydroxy-3-(phenoxymethyl)-1H-pyrazol-1- C BD A yl)isonicotinic acid 11 2-(5-hydroxy-1H-pyrazol-1-yl)isonicotinicacid A A B B 12 2-(5-p-tolyl-1H-pyrazol-1-yl)isonicotinic acid B B B B13 2-(5-m-tolyl-1H-pyrazol-1-yl)isonicotinic acid B B B 142-(5-(2,4-difluorophenyl)-1H-pyrazol-1-yl)iso- B B B B nicotinic acid 152-(5-(3,4-difluorophenyl)-1H-pyrazol-1-yl)iso- B B B nicotinic acid 162-(5-(3-fluorophenyl)-1H-pyrazol-1-yl)iso- B B B nicotinic acid 172-(5-(3-hydroxyphenyl)-1H-pyrazol-1-yl)iso- B B B B nicotinic acid 182-(5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)iso- B B B nicotinic acid 192-(5-(4-(methylsulfonyl)phenyl)-1H-pyrazol-1- B B C yl)isonicotinic acid20 2-(5-(3-methoxy-4-methylphenyl)-1H-pyrazol-1- B B C yl)isonicotinicacid 21 2-(5-(3-hydroxy-4-methylphenyl)-1H-pyrazol-1- A A Byl)isonicotinic acid 22 2-(5-(4-chloro-3-methoxyphenyl)-1H-pyrazol-1- BB C yl)isonicotinic acid 232-(5-(4-chloro-3-hydroxyphenyl)-1H-pyrazol-1- B B C yl)isonicotinic acid24 2-[5-(1H-indazol-6-yl)-1H-pyrazol-1- B B C yl]pyridine-4-carboxylicacid 25 methyl 2-[5-(1H-indazol-6-yl)-1H-pyrazol-1-yl]pyridine-4-carboxylate 26 2-(5-phenyl-1H-pyrazol-1-yl)isonicotinicacid C C C 27 2-(5-(4-fluorophenyl)-1H-pyrazol-1-yl)iso- B B B Dnicotinic acid 28 2-(5-(3-hydroxy-4-(methylsulfonyl)phenyl)-1H- B B Cpyrazol-1-yl)isonicotinic acid 292-(3-methyl-5-p-tolyl-1H-pyrazol-1-yl)iso- C C C nicotinic acid 302-(3-ethyl-5-p-tolyl-1H-pyrazol-1-yl)iso- C B C nicotinic acid 312-(5-methyl-1H-pyrazol-1-yl)isonicotinic acid C C B 322-(5-benzyl-1H-pyrazol-1-yl)isonicotinic acid D D D C 332-(3-benzyl-1H-pyrazol-1-yl)isonicotinic acid C C C C 342-(5-phenethyl-1H-pyrazol-1-yl)isonicotinic acid C C D 352-(3-phenethyl-1H-pyrazol-1-yl)isonicotinic acid B B B B 362-(5-methyl-4-phenyl-1H-pyrazol-1-yl)iso- B B D nicotinic acid 372-(5-methoxy-3-methyl-1H-pyrazol-1-yl)iso- C C C nicotinic acid 382-(5-(benzyloxy)-3-methyl-1H-pyrazol-1-yl)iso- B A B nicotinic acid 392-(5-(benzyloxy)-1H-pyrazol-1-yl)iso- A A A A nicotinic acid 402-{5-[(4-fluorobenzyl)oxy]-1H- A A A Dpyrazol-1-yl}pyridine-4-carboxylic acid 412-{5-[(3-fluorobenzyl)oxy]-1H- A A A pyrazol-1-yl}pyridine-4-carboxylicacid 42 2-{5-[(3-methoxybenzyl)oxy]-1H- A A Apyrazol-1-yl}pyridine-4-carboxylic acid 432-{5-[(4-methoxybenzyl)oxy]-1H- A A B pyrazol-1-yl}pyridine-4-carboxylicacid 44 2-(5-butyl-1H-pyrazol-1-yl)isonicotinic acid C C D 452-(3-butyl-1H-pyrazol-1-yl)pyridine-4-carboxylic B B B acid 462-(5-(4-bromophenyl)-1H-pyrazol-1-yl)iso- B B C nicotinic acid 472-{5-[4-(dimethylamino)phenyl]- B B C1H-pyrazol-1-yl}pyridine-4-carboxylic acid 482-[3-amino-5-(4-methylphenyl)-1H- A B Cpyrazol-1-yl]pyridine-4-carboxylic acid 492-[5-(1H-indazol-6-ylmethoxy)-1H- B B C Bpyrazol-1-yl]pyridine-4-carboxylic acid 502-{5-[(1-methyl-1H-indazol-6-yl)methoxy]- A A B B1H-pyrazol-1-yl}pyridine-4-carboxylic acid 512-{5-[(1-methyl-1H-indazol-6-yl)methoxy]- A A B1H-pyrazol-1-yl}pyridine-4-carboxylic acid 522-{5-[(3,4-difluorobenzyl)oxy]-1H- A A Bpyrazol-1-yl}pyridine-4-carboxylic acid 532-{5-[(4-chlorobenzyl)oxy]-1H- A A A pyrazol-1-yl}pyridine-4-carboxylicacid 54 2-(5-{[4-(trifluoro- A A B methyl)benzyl]oxy}-1H-pyrazol-1-yl)pyridine-4-carboxylic acid 55 2-{5-[(4-methylbenzyl)oxy]-1H- A A AC pyrazol-1-yl}pyridine-4-carboxylic acid 562-{5-[(4-ethylbenzyl)oxy]-1H- A A B C pyrazol-1-yl}pyridine-4-carboxylicacid 57 2-{5-[(4-bromobenzyl)oxy]-1H- A A Apyrazol-1-yl}pyridine-4-carboxylic acid 582-{5-[(3-chlorobenzyl)oxy]-1H- A A A pyrazol-1-yl}pyridine-4-carboxylicacid 59 2-{5-[(2-fluorobenzyl)oxy]-1H- A A Apyrazol-1-yl}pyridine-4-carboxylic acid 602-[5-(pyridin-3-ylmethoxy)-1H-pyrazol- A A B 1-yl]pyridine-4-carboxylicacid 61 2-[5-(pyridin-4-ylmethoxy)-1H-pyrazol- A A A1-yl]pyridine-4-carboxylic acid 62 methyl 2-{5-[(4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 63 methyl2-{5-[(3,4-difluorobenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate64 methyl 2-{5-[(4-chlorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 65 methyl 2-(5-{[4-(trifluoro-methyl)benzyl]oxy}-1H-pyrazol- 1-yl)pyridine-4-carboxylate 66 methyl2-{5-[(4-methylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate 67methyl 2-{5-[(4-ethylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate68 methyl 2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 69 methyl2-[5-(benzyloxy)-1H-pyrazol-1- yl]pyridine-4-carboxylate 70 methyl2-{5-[(3-fluorobenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate 712-{5-[(4,4-difluorocyclo- A A B hexyl)methoxy]-1H-pyrazol-1-yl}pyridine-4-carboxylic acid 72 2-{5-[(3-bromobenzyl)oxy]-1H- A A Apyrazol-1-yl}pyridine-4-carboxylic acid 732-{5-[(3-hydroxybenzyl)oxy]-1H- A A A pyrazol-1-yl}pyridine-4-carboxylicacid 74 2-{5-[(4-chloro-3-fluorobenzyl)oxy]- A A A1H-pyrazol-1-yl}pyridine-4-carboxylic acid 752-{5-[(4-chloro-2-fluorobenzyl)oxy]- A A A1H-pyrazol-1-yl}pyridine-4-carboxylic acid 762-{5-[(3-chloro-4-fluorobenzyl)oxy]- A A A1H-pyrazol-1-yl}pyridine-4-carboxylic acid 772-{5-[(4-cyclopropylbenzyl)oxy]- A A B1H-pyrazol-1-yl}pyridine-4-carboxylic acid 78 methyl2-{5-[(4-chloro-3-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 79 methyl2-{5-[(4-chloro-2-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 80 methyl2-{5-[(3-chloro-4-fluorobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate 81 methyl2-{5-[(4-cyclopropylbenzyl)oxy]- 1H-pyrazol-1-yl}pyridine-4-carboxylate82 2-[5-[1-(4-fluorophenyl)ethoxy]pyrazol- A A B1-yl]pyridine-4-carboxylic acid 832-[5-[(3,3-difluorocyclobutyl)methoxy]pyrazol- A A A1-yl]pyridine-4-carboxylic acid 84 2-[5-[(4-fluorophenyl)methoxy]- A A B4-methylpyrazol-1-yl]pyridine- 4-carboxylic acid 852-[4-ethyl-5-[(4-fluoro- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 86 2-[5-[(2,4-difluoro- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 872-[5-[(3,4-dichloro- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 88 2-[5-[(2,4-dichloro- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 892-[5-[(4-chloro-2-methyl- A A B B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 90 2-[5-[(4-chloro-2-methoxy- A A Aphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 912-[5-[[4-chloro-3-(trifluoro- A A B methyl)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 92 2-[5-[(3-chloro-4-methyl- A A A Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 932-[5-[(3-fluoro-4-methyl- A A A phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 94 2-[5-[(2,3-difluoro-4-methyl- A A Aphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 952-[5-[(3-chloro-4-ethyl- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 96 2-[5-[(4-ethyl-3-fluoro- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 972-[5-[(3-cyano- A A A phenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylicacid 98 methyl 2-[5-[(4-cyano- phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 99 2-[5-[(4-cyano- A A A Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 100 methyl2-[5-[(3-chloro-4-methyl- phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 101 methyl 2-[5-[(3-fluoro-4-methyl-phenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylate 102 methyl2-[5-[(3-chloro-4-ethyl- phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 103 methyl 2-[5-[(2,3-difluoro-4-methyl-phenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylate 104 methyl2-[5-[(4-ethyl-3-fluoro- phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate 105 2-[5-[(4-chloro-2-phenyl-methoxy- A A B Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1062-[5-[[4-chloro-2-(cyclopropyl- A A B C methoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 107 2-[5-[(4-chloro-2-propoxy-phenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1082-[5-[[4-chloro-2-(2,2,2-tri- A A B Cfluoroethoxy)phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1092-[5-[(4-fluorophenyl)methoxy]- A A C4-(2-hydroxyethyl)pyrazol-1-yl]pyridine- 4-carboxylic acid 1102-[4-[2-(dimethylamino)ethyl]- A A B 5-[(4-fluorophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 111 2-[5-[(2-butoxy-4-chloro- B B C C Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1122-[5-[[4-chloro-2-(2-methyl- B B C C C propoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 113 2-[5-[(4-chloro-2-propan-2-yloxy- BB C phenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1142-[5-[(2-butan-2-yloxy-4-chloro- B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1152-[5-[(4-chloro-2-ethoxy- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 116 2-[5-[[4-chloro-2-(2-methoxy- A A Bethoxy)phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1172-[5-[[4-chloro-2-[(4-fluoro- B B C C Cphenyl)methoxy]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid118 2-[5-[[4-fluoro-2-[(4-fluoro- A A B B Cphenyl)methoxy]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid119 2-[5-[[4-fluoro-2-[(E)-2-(4- B B C fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1202-[5-[[4-chloro-2-[(E)-2-(4- B B C fluorophenyl)ethenyl]phenyl]methoxy]pyrazol-1-yl]pyridine-4- carboxylic acid 1212-[5-[[4-fluoro-2-[2-(4-fluoro B B Cphenyl)ethyl]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1222-[5-[[4-chloro-2-[2-(4-fluoro- B B Cphenyl)ethyl]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1232-[5-(2,3-dihydro-1-benzofuran- A A B 7-ylmethoxy)pyrazol-1-yl]pyridine-4-carboxylic acid 124 2-[5-[(2,2-dimethyl-3H-1-benzofuran- B A B7-yl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1252-[5-[(4-cyano-2-methyl- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 126 2-[5-[(4-cyano-2-ethyl- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1272-[5-[(4-chloro-2-ethyl- B B C phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 128 2-[5-[(4-fluoro-2-methyl- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1292-[5-[(2-ethyl-4-fluoro- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 130 2-[5-[(2-chloro-4-methyl- B B C B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1312-[5-[(2-fluoro-4-methyl- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 132 2-[5-[(2,4-dimethyl- A A B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1332-[5-[(2-methoxy-4-methyl- A A B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1342-[5-[(2-cyano-4-methyl- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 135 2-[5-[(2-ethyl-4-methyl- B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1362-[5-[[4-chloro-2-(1-phenyl- B B C ethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 137 2-[5-[[4-fluoro-2-(1-phenyl- B B Cethoxy)phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1382-[5-[[4-chloro-3-[(4-fluoro- A A Bphenyl)methoxy]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid139 2-[5-[[4-fluoro-3-[(4-fluoro- A A Bphenyl)methoxy]phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid140 2-[5-[[4-chloro-3-(cyclopropyl- B B B B Cmethoxy)phenyl]methoxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1412-[5-[[4-chloro-3-(2,2,2-tri- A A B fluoroethoxy)phenyl]methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 142 2-[5-[(4-bromo-2-methyl- B B Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1432-[5-[(4-bromo-2-methoxy- A A B phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 144 2-[5-[(4-iodo-2-methyl- A A Bphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1452-[5-[(4-iodo-2-methoxy- A A B phenyl)methoxy]pyraol-1-yl]pyridine-4-carboxylic acid 146 2-[5-[(5-fluoro-2,3-dihydro-1H-inden- B B B1-yl)oxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1472-[5-[(5-chloro-2,3-dihydro-1H-inden- B B C1-yl)oxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1482-[5-[(6-fluoro-1,2,3,4-tetra- B B C hydronaphthalen-1-yl)oxy]pyrazol-1-yl]pyridine-4-carboxylic acid 149 2-[5-[(6-chloro-1,2,3,4-tetra- B A Chydronaphthalen-1-yl)oxy]pyrazol- 1-yl]pyridine-4-carboxylic acid 1502-[5-[(2-chloro-4-ethyl- B B C phenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid 151 2-[5-[(4-ethyl-2-fluoro- B A Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1522-[5-[(2-chloro-4-cyclopropyl- B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1532-[5-[(4-cyclopropyl-2-fluoro- B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1542-[5-[(3-chloro-4-cyclopropyl- B B Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1552-[5-[(4-cyclopropyl-3-fluoro- B A Cphenyl)methoxy]pyrazol-1-yl]pyridine- 4-carboxylic acid 1562-[4-[2-[(4-fluorophenyl)methyl- A A A D methylamino]ethyl]pyrazol-1-yl]pyridine-4-carboxylic acid 157 N-cyano-2-[4-[2-[(4-fluoro- A A Aphenyl)methylmethylamino]ethyl]pyrazol- 1-yl]pyridine-4-carboxamide 1582-[3-(4-chlorophenyl)-5-hydroxypyrazol- C C C C A1-yl]pyridine-4-carboxylic acid 1592-[3-(3-chlorophenyl)-5-hydroxypyrazol- C C C D A1-yl]pyridine-4-carboxylic acid 160 2-(3-cyclopentyl-5-hydroxypyrazol- CB C D A 1-yl)pyridine-4-carboxylic acid 1612-[3-[(2,6-difluorophenyl)methyl]- C A 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 162 2-[5-hydroxy-3-(1-phenylethyl)pyrazol- C C D A1-yl]pyridine-4-carboxylic acid 163 2-[3-[(2-chlorophenyl)methyl]- C C DA 5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1642-[3-[(3-chlorophenyl)methyl]- C C D A 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 165 2-[3-[(4-chlorophenyl)methyl]- B C D A5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1665-(1-phenylethyl)-2-[4-(1H-tetrazol- C A 5-yl)pyridin-2-yl]pyrazol-3-ol167 5-[(2-chlorophenyl)methyl]-2-[4-(1H- C Atetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 1685-[(3-chlorophenyl)methyl]-2-[4-(1H- C Atetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 1695-[(4-chlorophenyl)methyl]-2-[4-(1H- C C D Atetrazol-5-yl)pyridin-2-yl]pyrazol-3-ol 1702-[3-[2-(4-chlorophenyl)propan-2-yl]- C A5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1712-[3-[1-(4-chlorophenyl)cyclopropyl]- C A5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1722-[3-[(3,5-dichlorophenyl)methyl]- C B 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid 173 2-[3-[(4-fluoro-2-methylphenyl)methyl]- C A5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1742-[3-[(2-fluoro-4-methylphenyl)methyl]- C A5-hydroxypyrazol-1-yl]pyridine- 4-carboxylic acid 1752-[3-[(2,4-difluorophenyl)methyl]- C A 5-hydroxypyrazol-1-yl]pyridine-4-carboxylic acid Note: Biochemical assay IC₅₀ data are designatedwithin the following ranges: A: ≦0.10 μM B: >0.10 μM to ≦1.0 μM C: >1.0μM to ≦10 μM D: >10 μM

Example 2 In Vitro Cell-based Assay

An assay to measure the degree of cellular inhibition of KDM5A and 5Bwas developed. This quantitative immuno-blotting assay measures theamount tri-methylated histone H3 at amino acid Lysine number 4, aspecific substrate and product of the direct enzymatic activity of thehistone demethylases KDM5A and KDM5B from extracts of the ZR-75-1 breastcancer cell line. Upon analysis a correlation was observed between theinhibition of these enzymes in a biochemical assay and the degree ofinhibition of these enzymes within cancer cell lines.

Assay Principle

This assay is a fluorometric immunoassay for the quantification oftri-methyl H3K4 extracted from cells treated with test compound and isused as a measure of the cellular inhibition of KDM5A/B.

Assay Method

ZR-75-1 (PTEN null, ER+) breast cancer cells numbering 50,000 (ATCC)were seeded into each well of a 96-well tissue culture treated plate andthen exposed to an 11 point dilution of test compound with finalconcentration ranges of test compound ranging from 2000 uM to 10 nM.Cells were left in the presence of test compound for 72 hours. Extractswere prepared containing all of the cellular histone material usingdetergent based lysis and sonication methods. These lysates weresubsequently normalized for total protein content using a colorimetricbicinchonic acid assay (MicroBCA Pierce/Thermo Scientific). Normalizedcell extracts were then subjected to typical immuno-blotting proceduresusing NuPage reagents (Life Technologies). Electrophoretically separatedhistones were then transferred and immobilized using polyvinylidenedifluoride membrane (Immobilon-FL Millipore). The amount oftri-methylated lysine 4 of histone H3 was detected using an antibodyspecific to the tri-methylated state (Cell Signaling Technologies) andquantified on an infrared imager using a densitometry software package(Odyssey CLx, Image Studio, Li-Cor). This background subtracteddensitometry value was reported as a ration of the GAPDH amount for thatsample and then calculated as a percent of the DMSO treated sample. Thesoftware package XL-fit (IDBS) was then used to calculate a relativeIC₅₀ value for the dilution series of a given test compound according tothe equation: fit=(D+((Vmax*(x^n))/((x^n)+(Km^n)))).

Table 4 provides the cellular IC₅₀ values of various compounds disclosedherein.

TABLE 4 Example Cellular IC₅₀ (μM) 39 C 40 B 41 D 50 D 52 B 53 B 55 B 56B 57 B 58 B 62 C 63 B 64 B 71 C 72 C 74 C 75 C 76 C 86 C 87 B 89 A 90 B92 B 93 B 94 C 98 C 99 B 115 B 117 C 118 C 121 C 124 D 125 C 126 D 127 C128 B 129 C 130 C 131 C 132 B 133 B 134 C 136 C 137 C 138 C 139 B 140 C141 C 142 C 144 C 145 C 151 C Note: Cellular assay IC₅₀ data aredesignated within the following ranges: A: ≦0.10 μM B: >0.10 μM to ≦1.0μM C: >1.0 μM to ≦10 μM D: >10 μM

Example 3 In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-β Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study. Atthe conclusion of the treatment period, plasma and tumor samples aretaken for pharmacokinetic and pharmacodynamic analyses, respectively.

III. Preparation of Pharmaceutical Dosage Forms Example 1 Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula (I)or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen,halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, orheteroarylalkyl; R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl; R³ is hydrogen, halogen,—N(R⁵)₂, OR⁶, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl; R⁴ ishydrogen or alkyl; and wherein each R⁵ is independently hydrogen, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl, and each R⁶ isindependently alkyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl,aralkyl, or heteroarylalkyl; with the provision: if R² and R³ are bothhydrogen, then R¹ is not hydrogen, methyl, trifluoromethyl, isopropyl,or cyclopropyl; or if R¹ and R³ are both hydrogen, then R² is notmethyl, trifluoromethyl, bromine, or chlorine; or if R¹ and R³ are bothmethyl, then R² is not hydrogen, methyl, or ethyl; or if R¹ and R² arehydrogen, then R³ is not


2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is hydrogen.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is alkyl.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is C₂-C₁₀ alkyl.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is aralkyl.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is —OR⁶.
 7. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl.
 8. The compound of claim6, or a pharmaceutically acceptable salt thereof, wherein R⁶ is aralkylor heteroarylalkyl.
 9. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is carbocyclylalkyl orheterocyclylalkyl.
 10. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is aryl.
 11. The compound of claim6, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areboth hydrogen.
 12. The compound of claim 6, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is hydrogen.
 13. The compound ofclaim 6, or a pharmaceutically acceptable salt thereof, wherein R² ishydrogen.
 14. The compound of claim 7, or a pharmaceutically acceptablesalt thereof, wherein R¹ and R² are both hydrogen.
 15. The compound ofclaim 10, or a pharmaceutically acceptable salt thereof, wherein R¹ andR² are both hydrogen.
 16. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R³ is phenylsubstituted with at least one substituent selected from alkyl, halogen,hydroxy, alkoxy, or alkylsulfone.
 17. The compound of claim 16, or apharmaceutically acceptable salt thereof, wherein R³ is phenylsubstituted at the 4-position.
 18. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound ofFormula (I) as described in claim 1, or a pharmaceutically acceptablesalt thereof.
 19. A method for inhibiting a histone-demethylase enzymecomprising contacting a histone demethylase enzyme with a compound ofFormula (I) as described in claim
 1. 20. A method for treating cancer insubject in need thereof comprising administering to the subject acomposition comprising a compound of Formula (I) as described in claim1, or pharmaceutically acceptable salt thereof.
 21. A compound ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen,halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, carbocyclylalkyl, heterocyclylalkyl, aralkyl, orheteroarylalkyl; R² is hydrogen, halogen, —OH, —OR⁵, —N(R⁵)₂, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl; R³ is hydrogen, halogen,—N(R⁵)₂, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,carbocyclylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl; R⁴ ishydrogen or alkyl; and each R⁵ is independently hydrogen, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclylalkyl,heterocyclylalkyl, aralkyl, or heteroarylalkyl; with the proviso that:if R² and R³ are both hydrogen, then R¹ is not hydrogen, methyl,trifluoromethyl, isopropyl, or cyclopropyl; or if R¹ and R³ are bothhydrogen, then R² is not methyl, trifluoromethyl, bromine, or chlorine;or if R¹ and R³ are both methyl, then R² is not hydrogen, methyl, orethyl; or if R¹ and R² are hydrogen, then R³ is not


22. A pharmaceutical composition comprising the compound of claim 21, ora pharmaceutically acceptable salt thereof.